Cancer stem cells: The root of all evil? [Archive]

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Rich66

04-16-2009, 05:54 PM

University of Michigan (home of Dr. Max Wicha)
cancer stem cell website (http://www.mcancer.org/stemcells/): http://www.mcancer.org/stemcells/ (http://www.mcancer.org/stemcells/)

Cancer stem cells
The root of all evil?
Sep 11th 2008
From The Economist print edition

Cancer may be caused by stem cells gone bad. If that proves to be correct, it should revolutionise treatment
Get article background (http://www.economist.com/background/displayBackground.cfm?story_id=12202589)
MUCH of medical research is a hard slog for small reward. But, just occasionally, a finding revolutionises the field and cracks open a whole range of diseases. The discovery in the 19th century that many illnesses are caused by bacteria was one such. The unravelling of Mendelian genetics was another. It now seems likely that medical science is on the brink of a finding of equal significance. The underlying biology of that scourge of modern humanity, cancer, looks as though it is about to yield its main secret. If it does, it is possible that the headline-writer’s cliché, “a cure for cancer”, will come true over the years, just as the antibiotics that followed from the discovery of bacteria swept away previously lethal infectious diseases.
The discovery—or, rather, the hypothesis that is now being tested—is that cancers grow from stem cells in the way that healthy organs do. A stem cell is one that, when it divides, produces two unequal daughters. One remains a stem cell while the other multiplies into the sorts of cells required by its organ. This matters for cancer because, at the moment, all the cells of a tumour are seen as more or less equivalent. Therapies designed to kill them do not distinguish between them. Success is defined as eliminating as many of them as possible, so those therapies have been refined to do just that. However, if all that the therapies are doing is killing the descendants of the non-stem-cell daughters, the problem has not been eliminated. Instead of attacking the many, you have to attack the few. That means aiming at the stem cells themselves.
Not all investigators support the cancer-stem-cell hypothesis, but the share who do so is growing rapidly. A mere five years ago, few research papers on the subject were presented at big academic meetings. This year there were hundreds at one such meeting alone. Moreover, data from clinical trials based on the hypothesis suggest that it has real value for patients. As a result, drug companies have taken notice and are trying to develop substances that will kill cancer stem cells.

The virtues of self-restraint
The root cause of both cancer and stem cells is multicellularity. In the distant past, when all living things had only one cell, that cell’s reproduction was at a premium. In the body of an animal, however, most cells have taken a vow of self-denial. Reproduction is delegated to the sex cells. The rest, called somatic cells, are merely supporting actors, specialised for the tasks needed to give the sex cells a chance to get into the next generation. For this to happen required the evolution of genes that were able to curb several billion years’ worth of instinct to proliferate without killing that instinct entirely. Only then could somatic cells do their job, and be present in appropriate numbers.
The standard model of tumour formation was based on the fact that somatic cells slowly accumulate mutations. Sometimes these disable the anti-proliferation genes. If enough of the brakes come off in a somatic cell, so the theory went, it will recover its ancestral vigour and start growing into a tumour. Cancer, then, is an inevitable cost of being multicellular.
The discovery of stem cells changed this picture subtly, but importantly. Blood stem cells were found a long time ago, but only recently has it become apparent that all tissues have stem cells. The instincts of stem cells lie halfway between those of sex cells and ordinary body cells. They never stop reproducing, but they cannot look forward to making the generational leap. When the body dies, so do they. However, they are few in number, and because at cell division only one daughter continues to be a stem cell, that number does not grow.
This division of labour may even be another type of anti-cancer mechanism. It allows stringent locks to be put on somatic cells (which, for example, strictly limit the number of times they can divide), yet it permits tissue to be renewed. Without stem cells, such tissue-renewal would be the province of any and every somatic cell—a recipe, as the traditional model observes, for tumorous disaster. The obverse of this, however, is that if a stem cell does mutate into something bad, it is likely to be very bad indeed. That, in essence, is the stem-cell hypothesis of cancer.

One obvious prediction of this hypothesis is that tumours will have at least two sorts of cell in them: a dominant population of daughter cells and a minority one of stem cells. The first person to show that to be true was John Dick, a molecular biologist at the University of Toronto. In 1997 he isolated what looked like stem cells from a blood cancer called acute myeloid leukaemia (AML). Blood cancers are easier to deal with in this context than solid tumours because their cells do not have to be separated from one another before they are examined. One characteristic of AML cells is that they have two sorts of a protein, called CD34 and CD38, on their surfaces. Dr Dick thus used two sets of special antibodies for his experiment. One sort stuck only to the CD34 molecule, the other only to CD38. Each sort was also attached to a fluorescent tag.
By mixing the AML cells from his patients with the two antibodies and running them through a machine that sorted them according to how they fluoresced, he showed that most were positive for both proteins. However, a small fraction (as low as 0.2%) were positive only for CD34. These, he suspected, were the stem cells.
He was able to confirm this by injecting the minority cells into mice. The resulting tumours had the same mix of cells as those from human patients. However, when he injected mice with samples from the majority cells, with both sorts of the protein, no tumours resulted. The CD34-only cells thus acted as cancer stem cells.
Moreover, this phenomenon was not confined to leukaemia. In 2003 a group of researchers at the University of Michigan in Ann Arbor, led by Max Wicha and Michael Clarke, used a similar trick on breast-cancer cells. In this case the surface proteins were known as CD24 and CD44, and the minority were those positive only for CD44. As with AML, these minority cells produced cancers in mice, whereas the majority cells did not.
Since these two pieces of work, the list of cancer stem cells has multiplied. It now includes tumours of the breast, brain, prostate, colon, pancreas, ovary, lung, bladder, head and neck, as well as melanoma, sarcoma, AML, chronic myelogenous leukaemia, Hodgkin’s lymphoma and myeloma.
That is quite a list. The question is, what can be done with it? Jeremy Rich, a neurologist at Duke University in Durham, North Carolina, has one idea. He created mice that had human glioblastoma tumours, a form of brain cancer, growing in them. Then he treated these mice with radiation (the standard therapy for such cancer in people). He found that the cancer stem cells were more likely to survive this treatment than the other cells in the tumour. That turned out to be because, although all the tumour cells suffered equal amounts of DNA damage from the radiation, the stem cells were better able to repair this damage. When he treated the mice simultaneously with radiation and with a drug that interferes with DNA repair, however, the stem cells no longer had an advantage. They were killed by the radiation along with the other cells.
If that result applies to people as well as rodents, it opens up a whole avenue of possibility. In fact, Dr Rich is now in negotiations with several companies, with a view to testing the idea in humans. That “if” is a real one, though. A mouse is not a human being.
Indeed, the stem-cell hypothesis is often criticised for its reliance on animal models of disease. Some researchers worry that the experiments used to identify putative cancer stem cells are too far removed from reality—human tumour cells do not naturally need to survive in mice—and thus may not reflect human cancer biology at all.
Proponents of the hypothesis are alive to that concern, but they think that the same pattern has been seen so often in so many different cancers that it is unlikely to be completely wrong. The practical test, though, will be whether the hypothesis and ideas that emanate from it, such as Dr Rich’s combination therapy, actually help patients survive.

Searching for the suspects
As a step towards discovering whether they do, William Matsui, an oncologist at Johns Hopkins University School of Medicine in Baltimore, looked for cancer stem cells in pancreatic-tumour samples taken from nearly 300 patients. His team found that patients whose tumours did contain such stem cells survived for an average of 14 months. Those whose tumours lacked them survived for 18 months.
That finding is consistent with the idea that cancer stem cells contribute to the most aggressive forms of the disease, though it does not prove they cause tumours in the first place. And although the absence of detectable stem cells in some tumours may be seen as casting doubt on the whole idea, it may instead be that they are too rare to be easily detected. If the stem-cell idea is confirmed, it may help doctors and patients choose how to treat different tumours. Those with detectable stem cells might be candidates for aggressive chemical and radiation therapies, while those without might best be treated with the surgeon’s knife alone.
Breast-cancer researchers are also testing the stem-cell hypothesisin the clinic. Jenny Chang’s group at Baylor College of Medicine, in Texas, took samples of tumours from women before and after standard chemotherapy. When they counted the cells in the tissue they found that the proportion of stem cells in a tumour increased after treatment. That suggests the chemotherapy was killing the non-stem tumour cells and leaving the stem cells behind. When the group repeated the experiment using a modern drug called Tykerb that blocks what is known as the HER2 pathway, they got a different result. HER2 is a gene which encodes a protein that acts as a receptor for molecules called growth factors which, as their name suggests, encourage cell growth and proliferation. After the HER2-blocking treatment, cancer stem cells formed the same proportion of the residual tumour as beforehand. That suggests they, too, were being clobbered by the new treatment. It is probably no coincidence that another drug, Herceptin, which also goes after HER2, is one of the few medicines that is able to prolong the lives of people with advanced cancer.
The stem-cell hypothesis has also changed the way people do basic research. For example, over the past few years cancer researchers have been grinding up pieces of tumour and using what are known as gene-expression microarrays to work out which genes are active in them. However, if the hypothesis is correct, this approach will probably yield the wrong result, because the crucial cells make up but a small part of a tumour’s bulk and the activity of their genes will be swamped by that of the genes of the more common non-stem cells. The answer is to isolate the stem cells before the grinding starts.
This approach has already yielded one important finding. When Dr Chang used microarrays to study gene expression in the CD44-positive cells from breast tumours, she noticed that they did not look like those of the epithelial cells that make up the bulk of such a tumour. Epithelial cells are immobile, grow in “cobblestone” patterns and produce proteins that help them stick together. The gene expression of the putative stem cells, however, resembled that of a mesenchymal cell. Mesenchymal cells rarely stick together. Indeed, they are mobile and are able to slip through the matrix of proteins that holds epithelial cells together.
That finding is important because mobile cells are more likely to escape from a tumour and form secondary cancers elsewhere in the body. Once such secondaries are established, successful treatment is much harder. And the CD44-positive cells also expressed genes that are important for stem-cell self-renewal, particularly one called Notch that controls the flow of chemical signals within a cell.
Researchers at OSI Pharmaceuticals, a firm that makes a drug called Tarceva, found a similar pattern in lung cancer. Several years ago, they started looking for gene-expression patterns that correlated with response to Tarceva. They found that tumours with a pattern that resembled epithelial cells were sensitive to the drug. By contrast, those that had a mesenchymal pattern were not. They hypothesised that as tumours develop, some of their cells actually switch from a sticky, epithelial state to a mobile, mesenchymal one. This epithelial-to-mesenchymal transition, or EMT, is well known to biologists who study embryonic development, but OSI’s results, and those of other researchers, suggest that cancers may have hijacked it for their own use.
Robert Weinberg, a molecular biologist at the Massachusetts Institute of Technology, and his colleagues have come to the same conclusion but they have taken the hypothesis one step further. They think that tumour cells which have undergone EMT have acquired many of the characteristics of cancer stem cells. Experiments in his laboratory, employing a variety of animal models of breast cancer, suggest that communication between tumour cells and surrounding non-cancerous support cells can lead some of the cancer cells to undergo EMT.
That is intriguing. If this transition really can be induced in tumour cells, then any of them might be able to become a cancer stem cell. So it may be that the fundamentalist version of the stem-cell hypothesis is wrong, and the stem cells are a result of a cancer, rather than its cause. That could be another reason why Dr Matsui found that pancreatic cancers do not always seem to contain stem cells.
Dr Weinberg is sensitive to this point, and is cautious when talking about these experiments. He refers to the cells that have undergone EMT as “having the qualities of stem cells” but avoids actually calling them cancer stem cells. If his idea is correct, though, it means that finding drugs which block the signals that induce EMT could reduce the stem-cell population and prolong the survival of the patient. It also means that both the epithelial cells and the mesenchymal ones will have to be attacked. And OSI is now testing a drug that does just that.

Notch up a victory?
Breast-cancer researchers, too, are testing drugs that hit molecular targets highlighted by cancer-stem-cell studies. Merck, for example, has turned to a drug it originally developed to treat Alzheimer’s disease. Although this drug, code-named MK0752, did not slow that disease, it does block activity of Notch, the stem-cell self-renewal gene, and might thus be an appropriate weapon against breast-cancer stem cells. Dr Chang and Dr Wicha have started a clinical trial which uses MK0752 in combination with standard chemotherapy. By the end of the year they hope to have some idea of whether the combination kills cancer cells in human tumours.
Attacking Notch is a high-risk approach, because this gene is used by healthy stem cells as well as cancerous ones; healthy organs as well as tumours could be damaged. Some researchers are therefore taking a different tack and looking for drugs that hit only the unhealthy stem cells. Craig Jordan, a biologist at the University of Rochester Medical Centre, in New York state, is one such. He has discovered that a chemical called parthenolide, found in feverfew, a medicinal plant, kills AML stem cells. Normal stem cells, however, seem to be able to tolerate the drug without difficulty. The reason is that the leukaemia cells are reliant on a biochemical pathway that parthenolide blocks, whereas normal stem cells are not. If all goes well, a trial to test the safety of a modified form of parthenolide will start in a few months.
If the safety issues can be dealt with—and most researchers think they can—then attacking cancer stem cells really could help patients survive. If, that is, the stem-cell hypothesis is correct.
At the moment, scientists being scientists, few are willing to be anything other than cautious. They have seen too many past cures for cancer vanish in a puff of smoke. The proof needs to come from patients—preferably with them living longer. But if the stem-cell hypothesis is indeed shown to be correct, it will have the great virtue of unifying and simplifying the understanding of what cancer is. And that alone is reason for hope.

Comments from article readers:
http://www.economist.com/science/displayStory.cfm?story_id=12202589

eric

04-16-2009, 06:38 PM

Since I've read about cancer stem cells I've felt that killing them is the key to curing or managing the disease.

Rich66

04-16-2009, 06:42 PM

Cancer stem cells

On the move
Jun 5th 2008 | CHICAGO
From The Economist print edition

Organ-transplant data provide more evidence that stem cells cause cancer
DOCTORS track the long-term health of organ-transplant patients in registries. Such registries make it possible to uncover trends or long-term problems in the population that may be missed in smaller samples. But they can also be pressed into service to support basic research. And a group of researchers led by Sanford Barsky of Ohio State University College of Medicine in Columbus has done just that. As they reported on June 2nd to a meeting of the American Society of Clinical Oncology, in Chicago, they have used one such registry to support the increasingly popular idea that many if not all cancers are caused by stem cells gone bad.
Each organ and tissue in the body has its own collection of stem cells. When these cells divide, they produce two very different daughter cells. One resembles the parent stem cell and thus allows the whole process to continue. The progeny of the other differentiate into mature cells within the skin, kidney, lung or what have you. This is how organs renew themselves over the life of an individual. In a healthy organ, the stem cells divide only when needed—usually in response to injury or when other cells have died. Some cancer scientists, however, think that stem cells can lose this control function and thus divide endlessly, leading to tumours.
Dr Barsky reasoned that if the cancer stem-cell hypothesis is true, then stem cells from a donor organ may cause cancer somewhere else in a transplant recipient's body. Looking in a patient registry, he identified 280 people who had undergone an organ transplant and later developed a solid tumour. In nearly half of these cases donor and recipient were of different sexes, which means the cells from each would have different sex chromosomes (women have two X chromosomes, men an X and a Y). That makes a cancer derived from the transplant easy to identify.
To find out if the tumour cells were the same sex as the body they inhabited, Dr Barsky labelled slices of tumour with green fluorescent tags that bind to the X chromosome and red tags that bind to the Y. And he found transplant-derived cancers in abundance: in 12% of cases, the sex of the tumour matched the donor rather than the recipient. For example, a 48-year-old woman developed skin cancer nine months after receiving a bone-marrow transplant from a man. The tumour cells had a Y chromosome, indicating that the cancer arose from the donated bone marrow. In another case, a 62-year-old man developed colon cancer ten years after receiving a kidney transplant from a female donor. The colon-cancer cells lacked a Y chromosome.
Closer examination of the DNA in the tumour cells and surrounding tissue showed that the tumours definitely did originate from the donor organs, not the recipients. Dr Barsky also found that if a tumour formed in the transplanted organ, it could be derived from either recipient or donor cells.
In each of these cases, the tumour that formed resembled any other tumour that would form in that site. The 48-year-old woman's looked like skin cancer, not cancer of the bone marrow. The 62-year-old man's looked like colon cancer and not like a kidney tumour. Thus, once a cell migrated to a new site, it took on the behaviour and appearance appropriate to that location—losing the identity it had held in its organ of origin.
This observation does not absolutely prove that the migrating cells are stem cells, but it would be astonishing if fully differentiated cells from one tissue could up sticks to another organ and then take on the characteristics of that organ. Besides, biologists do know that stem cells in the bone marrow move into the blood stream. Thus the formation of donor-derived tumours in distant tissues after a bone-marrow transplant is not entirely unexpected. A few reports also exist in the medical literature of donor-derived tumours arising after a solid organ, such as a liver or a kidney, has been transplanted. Dr Barsky's data, though, show that this is not such a rare event after all. Stem cells in one organ thus seem malleable enough to adopt a whole new developmental programme in another organ, even late in a person's life.
More important, though, in Dr Barsky's opinion, is that the new data support the idea that tumours arise from stem cells that have gone wrong. It is not clear whether those stem cells are healthy when they migrate to a new site and mutate into cancer stem cells after they have taken up residence, or if they mutate first and then migrate. Either way, however, transplant registries may just have shed light on a fundamental question in cancer biology.

Rich66

05-22-2009, 03:56 PM

OU Cancer Institute scientists’ discovery could help treat cancer

May 22, 2009
TULSA – A new discovery could provide a major step closer to a cure for cancer.
University of Oklahoma Cancer Institute scientists discovered how stem cell proteins work in the growth of cancer.
Cancer researchers have known for some time certain proteins in cells cause tumors to grow, but they never completely understood why, according to the OU Cancer Institute.
Research from two scientists at the University of Oklahoma Health Sciences Center found a new cancer protein and discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.
Courtney Houchen, cancer biologist at the OU Cancer Institute, said it is the first evidence of a stem cell protein regulating a tumor suppressor.
“This is a great advancement for the field,” he said. “We have filed a patent for the work.”
This research is on the forefront of identifying and targeting cancer stem cells, said Robert Mannel, director of the OU Cancer Institute.
“Cancer stem cell research holds tremendous potential in the fight against cancer – it points to new avenues for cancer drug development,” he said.
When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced, the level of tumor suppressor went up and the tumor stopped growing.
Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.
By targeting the new protein, researchers can develop new therapies that will specifically target cancer stem cells and stop cancer from growing and reoccurring.
“What we are saying is that if you target this it will work,” said Houchen. “I am confident that if you develop a drug through this protein or through two other markers we have found, you’re going to treat a lot of cancers.”
The work revolves around the scientists’ belief that the answer to cancer lies in cancer stem cells, which are not targeted by current therapies.
Five years ago, the OU researchers were among a handful of scientists in the nation studying cancer stem cells. But in the last two years cancer stem cells have become a rapidly emerging field, according to the institute.
The latest research from the OU Cancer Institute will appear in the upcoming issue of the journal Gastroenterology.
OU Cancer Institute members are conducting more than 100 cancer research projects supported by more than $20 million.
“From here we would like to understand more about how the protein works and we would like to develop the drugs to target the cells in the cancer,” said Houchen. “We hope we can generate more funding to accelerate the research.”

Stem cell research could 'weed' out cancer

A breakthrough by British scientists could help attack the root cause of cancer in the same way that weeding helps your garden.
By Richard Alleyne (http://www.telegraph.co.uk/journalists/richard-alleyne/), Science Correspondent
Published: 7:30AM GMT 26 Jan 2010

The research could speed up attempts to wipe out cancer by targeting tumour stem cells that drive the disease.
A team from Oxford University has developed a new method of isolating cancer stem cells that can then be grown and studied in the laboratory.
 The technique could pave the way to developing drugs that attack cancer at its root.
Dr Trevor Yeung, from the Weatherall Institute of Molecular Medicine at Oxford University, said: "Cancer stem cells drive the growth of a tumour. If we could target treatments against these cells specifically, we should be able to eradicate cancer completely."
Until now research on cancer stem cells has been slow, since the cells are difficult to identify and isolate from tumours.
In the past scientists have tried to find cancer stem cells in tissue samples taken from patients.
The new research involves better ways of using molecular markers to identify cancer stem cells, and maintaining the cells in simple laboratory cultures.
Instead of using biopsy samples, the scientists worked with established bowel cancer cell lines.
They found that the proportion of cancer stem cells within different bowel cancers varies widely, with aggressive tumours containing higher numbers.
The research is reported today in the journal Proceedings of the National Academy of Sciences.
Dr Yeung said: "Radiotherapy and chemotherapy work against all rapidly dividing cells. But there is increasing evidence that cancer stem cells are more resistant than other cells to this treatment. Cancer stem cells that have not been eradicated can lead to later recurrence of cancer.
"It's like trying to weed the garden. It's no good just chopping off the leaves, we need to target the roots to stop the weeds coming back.
"People have assumed that cancer stem cells made up a small proportion of the cells in a tumour, but it is becoming increasingly clear that this is not correct. The most aggressive tumours can have a majority of cells that are cancer stem cells."

bejuce

05-22-2009, 05:41 PM

The Economist article mentions that Tykerb was shown to work on cancer stem cells - this is great news and shows the promise of this drub in breast cancer treatment. I'm currently taking in as part of my neoadjuvant chemo and hope that it's doing its job!

Thank you for posting all this research here.

Rich66

05-23-2009, 10:01 AM

The study by Chang, U of Michigan:
http://clinicaltrials.gov/ct2/show/NCT00645333

Phase I/II Study of MK-0752 Followed by Docetaxel in Advanced or Metastatic Breast Cancer
This study is currently recruiting participants.
Verified by University of Michigan Cancer Center, August 2008
First Received: March 24, 2008 Last Updated: August 8, 2008 History of Changes (http://clinicaltrials.gov/ct2/archive/NCT00645333)
<table class="data_table" style="margin: 2ex 0pt;" width="50%" border="1" cellpadding="5" cellspacing="0"> <tbody><tr> <th class="header3 pale_banner_color" align="right" nowrap="nowrap"> Sponsored by: </th> <td class="body2" align="left" nowrap="nowrap"> University of Michigan Cancer Center
</td> </tr> <tr> <th class="header3 pale_banner_color" align="right" nowrap="nowrap">Information provided by: </th> <td class="body2" align="left" nowrap="nowrap">University of Michigan Cancer Center</td> </tr> <tr> <th class="header3 pale_banner_color" align="right" nowrap="nowrap">ClinicalTrials.gov Identifier: </th> <td class="body2" align="left" nowrap="nowrap">NCT00645333</td> </tr> </tbody></table>
 http://clinicaltrials.gov/ct2/html/images/frame/triangle.gif Purpose New and better therapies for locally advanced and metastatic breast cancer are needed because, even if standard treatment is successful in shrinking the cancer, there is still a high chance that the cancer will recur. Recent research suggests that breast tumors have a small number of cells in them that are "breast cancer stem cells", which are very resistant to standard treatment. It is thought that the reason that many patients cannot be cured of their breast cancers is that the stem cells are unable to be killed and remain in the body after standard treatment. Laboratory research has shown that a new drug, MK-0752, can target stem cells and prevent tumor recurrences when the drug is combined with docetaxel, a chemotherapy drug commonly used to treat breast cancer.
We know that MK-0752 is safe when given by itself to people. We do not know if treatment with MK-0752 and docetaxel combined is safe or if it will kill "breast cancer stem cells" in people with breast cancer. This clinical trial is being done to determine the safety of several doses of MK-0752 in combination with docetaxel. Preliminary data about the effectiveness of MK-0752 in combination with docetaxel will be collected. Also, tumor biopsy samples will be taken from some patients who have tumors that can be easily biopsied. The samples will be used to perform research tests to help determine if the "breast cancer stem cells" are being killed by the drug combination.

 <table class="data_table" width="80%" border="1" cellpadding="5" cellspacing="0"> <tbody><tr align="left"> <th class="header3 pale_banner_color"> Condition (http://clinicaltrials.gov/ct2/help/conditions_desc) </th> <th class="header3 pale_banner_color"> Intervention (http://clinicaltrials.gov/ct2/help/interventions_desc) </th> <th class="header3 pale_banner_color"> Phase (http://clinicaltrials.gov/ct2/help/phase_desc) </th> </tr> <tr valign="top" align="left"> <td class="body3" nowrap="nowrap"> Metastatic Breast Cancer
</td> <td class="body3" nowrap="nowrap"> Drug: MK-0752 and Docetaxel
Drug: MK-0752
</td> <td class="body3" nowrap="nowrap"> Phase I
Phase II
</td> </tr> </tbody></table>

 Genetics Home Reference (http://ghr.nlm.nih.gov/) related topics: breast cancer (http://clinicaltrials.gov/ct2/bye/mQoPWw4lZXcilwpxudhWudNzlXNiZip90dcx5Q1PedcO9BUyzB 1gWBcGuBcHS.)
 MedlinePlus (http://www.nlm.nih.gov/medlineplus/) related topics: Breast Cancer (http://clinicaltrials.gov/ct2/bye/WQoPWw4lZX-i-iSxudhWudNzlXNiZip9m67PvQ7xzwhaLwS9pwNHkw-P0B7x061nuQoPmdt.) Cancer (http://clinicaltrials.gov/ct2/bye/uQoPWw4lZX-i-iSxudhWudNzlXNiZip9m67PvQ7xzwhaLwS90B7x061nuQoPmdt .)
 Drug Information (http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp) available for: Docetaxel (http://clinicaltrials.gov/ct2/bye/YQoPWw4lZXcPSi7iedN6ZXNxvdDxuQ7Ju6c9cXcPSi7iEd-yWB7EZ6o35Q1yzB-VuQUgEscxkd789Ph9061PkThHv.)
U.S. FDA Resources (http://clinicaltrials.gov/ct2/info/fdalinks)
<table class="layout_table" style="margin-bottom: 2ex;" border="0" cellpadding="0" cellspacing="0"> <tbody><tr valign="top"> <td nowrap="nowrap">Study Type:</td> <td style="padding-left: 1em;">Interventional</td> </tr> <tr valign="top"> <td nowrap="nowrap">Study Design:</td> <td style="padding-left: 1em;">Treatment, Open Label, Single Group Assignment</td> </tr> <tr valign="top"> <td style="padding-top: 2ex;" nowrap="nowrap">Official Title:</td> <td style="padding-left: 1em; padding-top: 2ex;">Phase I/II Trial of MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer: A Study by the Stem Cell Clinical Consortium</td> </tr> </tbody></table> 
Further study details as provided by University of Michigan Cancer Center:

 Primary Outcome Measures:

dose limiting toxicity (DLT) [ Time Frame: first 21 days ] [ Designated as safety issue: Yes ]

 Secondary Outcome Measures:

measurability of lesions, objective status at each evaluation,best response, performance status, CTC response [ Time Frame: course of study ] [ Designated as safety issue: No ]

<table class="layout_table" style="margin-bottom: 3ex;" border="0" cellpadding="0" cellspacing="0"> <tbody><tr valign="top"> <td nowrap="nowrap"> Estimated Enrollment:</td> <td style="padding-left: 1em;">30</td> </tr> <tr valign="top"> <td nowrap="nowrap"> Study Start Date:</td> <td style="padding-left: 1em;">February 2008</td> </tr> <tr valign="top"> <td nowrap="nowrap"> Estimated Study Completion Date:</td> <td style="padding-left: 1em;">March 2012</td> </tr> <tr valign="top"> <td nowrap="nowrap"> Estimated Primary Completion Date:</td> <td style="padding-left: 1em;">March 2012 (Final data collection date for primary outcome measure)</td> </tr> </tbody></table>  <table class="data_table" width="100%" border="1" cellpadding="5" cellspacing="0"> <tbody><tr align="left"> <th class="header3 pale_banner_color"> Arms (http://clinicaltrials.gov/ct2/help/arm_group_desc) </th> <th class="header3 pale_banner_color"> Assigned Interventions (http://clinicaltrials.gov/ct2/help/interventions_desc) </th> </tr> <tr valign="top" align="left"> <td class="body3"> 1: Experimental </td> <td class="body3"> Drug: MK-0752 and Docetaxel Dose Level MK-0752 Docetaxel Peg-filgrastim
1 300 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 2 450 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 3 600 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 4 800 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9

Drug: MK-0752 Dose Level MK-0752 Docetaxel Peg-filgrastim
1 300 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 2 450 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 3 600 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 4 800 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9

</td> </tr> </tbody></table>

 http://clinicaltrials.gov/ct2/html/images/frame/triangle.gif Eligibility

<table class="layout_table" border="0" cellpadding="0" cellspacing="0"> <tbody><tr> <td nowrap="nowrap">Ages Eligible for Study: </td> <td style="padding-left: 1em;">18 Years and older</td> </tr> <tr> <td nowrap="nowrap">Genders Eligible for Study: </td> <td style="padding-left: 1em;">Both</td> </tr> <tr> <td nowrap="nowrap">Accepts Healthy Volunteers: </td> <td style="padding-left: 1em;">No</td> </tr> </tbody></table> Criteria
Inclusion Criteria:

Men or women with metastatic (Stage IV) breast cancer, or with locally advanced breast cancer (Stages IIIA > 10 cm, or Stages IIIB and IIIC) that did not respond to first-line anthracycline-based chemotherapy, for whom docetaxel is a recommended therapy
Presence of measurable or evaluable disease
Adequate organ function
Ability to swallow intact study drug capsules
Zubrod Performance Status of 0-1 with at least a 3 month life expectancy
Appropriate time must have elapsed since prior anti-neoplastic therapy with resolution of acute toxicity.

Exclusion Criteria:

Concurrent treatment with hormonal therapy intended to treat cancer
Radiotherapy within 7 days prior to first dose
Symptomatic CNS, and/or epidural metastases or symptomatic carcinomatous meningitis or with radiation treatment completed within the past 8 weeks
Serious comorbid illness which will limit the ability of the patient to safely receive anticancer treatment
Patients who are pregnant or nursing
Confounding factors present to provide misinterpretation of data (i.e., concurrent malignancy)

 http://clinicaltrials.gov/ct2/html/images/frame/triangle.gif Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00645333

 Contacts
<table class="layout_table indent2" border="0" cellpadding="0" cellspacing="0"> <tbody><tr> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">Contact: Cancer Answer Line</td> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">1 800 865-1125</td> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">canceranswerline@umich.edu (canceranswerline%40umich.edu?subject=NCT00645333, %20UMCC%202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer)</td> </tr> <tr> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">Contact: Judith Luckhardt, R.N.</td> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">734 647-5345</td> <td style="padding: 1ex 1em 0px 0px;" nowrap="nowrap">jluck@umich.edu (jluck%40umich.edu?subject=NCT00645333,%20UMCC%202 006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer)</td> </tr> </tbody></table>
 Locations
<table class="layout_table indent2" border="0" cellpadding="0" cellspacing="0"> <tbody><tr><td colspan="2" class="header3" style="padding-top: 2ex;" nowrap="nowrap"> United States, Massachusetts</td></tr> <tr> <td style="padding: 1ex 1em 0px 2em;" nowrap="nowrap">Dana Farber Cancer Institute</td> <td class="header3" style="padding: 1ex 0px 0px 2em;" nowrap="nowrap">Recruiting</td> </tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Boston, Massachusetts, United States, 02115 </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Ian Krop, M.D., Ph.D. 616-632-5958 ikrop@partners.org (ikrop%40partners.org?subject=NCT00645333,%20UMCC% 202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Jason Russak 617 632-4915 jason_russak@dfci.harvard.edu (jason_russak%40dfci.harvard.edu?subject=NCT006453 33,%20UMCC%202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> <tr><td colspan="2" class="header3" style="padding-top: 2ex;" nowrap="nowrap"> United States, Michigan</td></tr> <tr> <td style="padding: 1ex 1em 0px 2em;" nowrap="nowrap">University of Michigan Cancer Center</td> <td class="header3" style="padding: 1ex 0px 0px 2em;" nowrap="nowrap">Recruiting</td> </tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Ann Arbor, Michigan, United States, 48109 </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Cancer Answer Line 800-865-1125 canceranswetline@umich.edu (canceranswetline%40umich.edu?subject=NCT00645333, %20UMCC%202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Judith Luckhardt, RN 734 647-5345 jluck@umich.edu (jluck%40umich.edu?subject=NCT00645333,%20UMCC%202 006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Principal Investigator: Anne F Schott, M.D. </td></tr> <tr><td colspan="2" class="header3" style="padding-top: 2ex;" nowrap="nowrap"> United States, Texas</td></tr> <tr> <td style="padding: 1ex 1em 0px 2em;" nowrap="nowrap">Baylor College of Medicine</td> <td class="header3" style="padding: 1ex 0px 0px 2em;" nowrap="nowrap">Recruiting</td> </tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Houston, Texas, United States, 77030 </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Jenny Chang, M.D. 713-798-1905 jcchang@bcm.tmc.edu (jcchang%40bcm.tmc.edu?subject=NCT00645333,%20UMCC %202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> <tr><td colspan="2" style="padding-left: 4em;" nowrap="nowrap">Contact: Anne Pavlick, CRC ll 713 798-1975 acpavlic@bcm.tmc.edu (acpavlic%40bcm.tmc.edu?subject=NCT00645333,%20UMC C%202006.119,%20Phase%20I/II%20Study%20of%20MK-0752%20Followed%20by%20Docetaxel%20in%20Advanced%2 0or%20Metastatic%20Breast%20Cancer) </td></tr> </tbody></table>

Rich66

05-23-2009, 10:19 AM

<table width="100%" bgcolor="#ffffff" border="0" cellpadding="0" cellspacing="0"><tbody><tr></tr><tr><td> OSI Pharmaceuticals Provides Update on OSI-906 Data Being Presented on May 30th at the Upcoming Annual Meeting of the American Society of Clinical Oncology (ASCO)

<table width="100%" border="0" cellpadding="3" cellspacing="0"><tbody><tr></tr><tr><td class="dfont" bgcolor="#eeeeee">Posted : Fri, 15 May 2009 11:30:39 GMT</td></tr></tbody></table>
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</td> </tr> </tbody></table> MELVILLE, N.Y. - (Business Wire) OSI Pharmaceuticals, Inc. (NASDAQ: OSIP) announced today preliminary data from two Phase I dose escalation studies of oral OSI-906, a small molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors. The studies, along with a third on-going Phase I trial assessing OSI-906 in combination with Tarceva, comprise part of the Company’s principal oncology development program targeting the IGF-1R. The program also includes translational research and biomarker development activities around this highly attractive oncology target. In an intermittent oral dosing study, OSI-906 was well-tolerated up to doses of 450mg and has provided preliminary evidence of anti-tumor activity, with one confirmed partial response in an adrenocortical carcinoma (ACC) patient; one minor response in a patient with non-small cell lung cancer (NSCLC); 14 patients with stabilization of their disease for longer than 12 weeks including 7 patients with stabilization of their disease for longer than 24 weeks (out of 27 patients evaluable for tumor response to date). In a continuous dosing study, OSI-906 also had an acceptable safety profile and disease stabilization for longer than 12 weeks has been observed in 8 out of 29 patients evaluable for tumor response to date. Both Phase I studies continue to accrue patients at higher doses to determine the maximum tolerated dose (MTD) for both intermittent and continuous dosing of OSI-906, and to establish a recommended dose and dosing schedule for a Phase II clinical trial of OSI-906. “We believe these data, along with early data from an additional combination Phase I study with Tarceva, continue to position OSI-906 as a potential first-in-class small molecule inhibitor of the IGF-1R,” stated Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals. “Our extensive research around this crucial oncology signaling target has led us to develop a comprehensive development effort that includes targeting tumors such as ACC and ovarian cancer, where IGF-2 over-expression could indicate a particular dependence on this signaling pathway, and also NSCLC, where our understanding of EMT and compensatory signaling mechanism suggest that a Tarceva/OSI-906 combination could be particularly effective. With continued progress in our program we believe we could begin two registration-oriented trials – a monotherapy study in ACC in 2009 and a Tarceva combination study in NSCLC in 2010.”
The OSI-906 Phase I single-agent data will be presented in two poster presentations at the Annual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, FL on May 30, 2009 between 8 a.m. and noon EDT (Abstracts #3544 and #2559).
Study Results
Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small molecule insulin like growth factor -1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors- C.P. Carden, et al. (Abstract #3544)
The primary objective of this study (OSI-906-102) is to determine the maximum tolerated dose (MTD) and recommended Phase II dose of oral OSI-906 for three intermittent dosing schedules: Schedule 1: days 1-3, every 14 days; Schedule 2: days 1-5, every 14 days; Schedule 3: days 1-7, every 14 days. Secondary objectives include safety profile, pharmacokinetics (PK) and pharmacodynamics (PD) profiles and preliminary anti-tumor activity.
Preliminary results from 33 patients evaluable to date showed that OSI-906 was well-tolerated up to doses of 450mg, with no dose limiting toxicities (DLTs) and no grade 3 or 4 toxicities reported to date. Most common adverse events were grade 1 rash, diarrhea, fatigue and peripheral edema. Frequency and severity of toxicities did not correlate with dose level. Two cases of hyperglycemia (one grade 1; one grade 2) were reported.
Encouraging anti-tumor activity was seen in the study, with one partial response in an ACC patient at the 450mg dose (in the Schedule 1 group), 14 patients with stable disease for ≥ 12 weeks including 7 patients with stable disease for ≥ 24 weeks. Of particular note, anti-tumor activity was seen in two ACC patients and one NSCLC patient:

One 2<sup>nd</sup>-line ACC patient, a 35-year old woman with metastatic disease, had a partial response (PR) confirmed at 16 weeks of treatment with OSI-906. No drug-related toxicities have been observed to date and this patient continues on therapy.
One 4<sup>th</sup>-line NSCLC patient, a 77-year old man with metastatic disease, had a minor response per the treating physician and a best response (per RECIST) of stable disease for 43 weeks.
One 3<sup>rd</sup>-line ACC patient had stable disease for 30 weeks.

The study authors also note that PK is dose-proportional up to 450mg. An exploratory analysis from glucose monitoring also indicates that significant hyperglycemia was not observed in patients in spite of hyperinsulinemia at higher doses.
The MTD in this study has not yet been reached and patient accrual is on-going.
Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors- C.R. Lindsay, et al. (Abstract #2559)
The primary objective of this study (OSI-906-101) is to determine the MTD and recommended Phase II dose of oral OSI-906 administered either once daily or twice daily. Secondary objectives also included safety profile, PK and PD profiles and preliminary anti-tumor activity.
Preliminary results from 37 patients with advanced solid tumors (9 colorectal, 6 pancreatic, 3 renal, 3 esophageal and 16 other tumor types) also show that continuous oral dosing of OSI-906, given either once or twice a day, has an acceptable safety profile. One recent DLT of asymptomatic grade 3 hyperglycemia was reported at the 450mg once-a-day dose, however, this patient was asymptomatic and glucose returned to normal by Day 2, and no dose interruptions or reductions were necessary. OSI-906 plasma concentrations exceed concentration required for anti-tumor efficacy in preclinical models, with twice-a-day dosing providing improved coverage above threshold. Further, PD target modulation and disease stabilization were observed. While no objective tumor responses have been reported to date, 8 patients had stable disease ≥ 12 weeks including 4 patients who had stable disease ≥ 24 weeks.
The MTD in this study has not yet been reached and patient accrual is on-going.
Additional Background on OSI-906
IGF-1 and IGF-2 are growth factors, or hormones, known to stimulate growth and survival of cancerous cells. IGF-1R has been viewed as an important therapeutic target due to its involvement in the growth and proliferation of a variety of human cancers, including colorectal, prostate, non-small cell lung, breast and ovarian cancers.
In preclinical studies, OSI-906 blocked the ability of IGF-1R to signal in xenograft mouse models of human colorectal cancer. Preclinical research also showed that colon cancer tumor cells respond to OSI-906 because they produce and are dependent on the growth-promoting effects of IGF-2. In addition to colorectal cancer, OSI-906 has also been shown to inhibit growth of human pancreatic and thyroid cancers in animal models. The IGF/IGF-1R signaling pathway has also been implicated in protecting tumor cells from apoptosis induced by a number of cytotoxic agents as well as molecular targeted therapies including EGFR inhibitors. Preclinical data also suggest that OSI-906 may be synergistic with Tarceva<sup> </sup>in non-small cell lung and pancreatic human tumor xenografts.
About OSI Pharmaceuticals
OSI Pharmaceuticals is committed to "shaping medicine and changing lives" by discovering, developing and commercializing high-quality, novel and differentiated targeted medicines designed to extend life and improve the quality of life for patients with cancer and diabetes/obesity. For additional information about OSI, please visit http://www.osip.com (http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.osip.com&esheet=5965534&lan=en_US&anchor=http%3A%2F%2Fwww.osip.com&index=1).
This news release contains forward-looking statements. These statements are subject to known and unknown risks and uncertainties that may cause actual future experience and results to differ materially from the statements made. Factors that might cause such a difference include, among others, OSI's and its collaborators' abilities to effectively market and sell Tarceva and to expand the approved indications for Tarceva, OSI’s ability to protect its intellectual property rights, safety concerns regarding Tarceva, competition to Tarceva and OSI’s drug candidates from other biotechnology and pharmaceutical companies, the completion of clinical trials, the effects of FDA and other governmental regulation, including pricing controls, OSI's ability to successfully develop and commercialize drug candidates, and other factors described in OSI Pharmaceuticals' filings with the Securities and Exchange Commission.

OSI Pharmaceuticals, Inc.
Investors/Media:
Kathy Galante, 631-962-2043
Senior Director
or
Media:
Kim Wittig, 631-962-2135
Director
or
Burns McClellan, Inc. (representing OSI)
Justin Jackson/Kathy Nugent (media)
212-213-0006

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Rich66

06-05-2009, 11:08 AM

Breast Cancer Stem Cells Seem to Survive Radiation Therapy

TUESDAY, Dec. 19 (HealthDay News) -- Breast cancer stem cells, a type of cell that scientists have recently discovered is difficult to kill, may be especially resistant to radiation therapy, a new study suggests.
In fact, the radiation can even increase the growth of these stubborn stem cells, report researchers from the University of California, Los Angeles, David Geffen School of Medicine.
"This population of stem cells is more radiation-resistant than are non-stem cells," said Dr. Frank Pajonk, an assistant adjunct professor of radiation oncology at UCLA and corresponding author on the study. "We are the first to report this."
Radiation treatment involves exposure to high-energy rays or particles that destroy cancerous cells. It is often recommended after surgery for breast cancer, according to the American Cancer Society.
Pajonk and his colleagues exposed breast cancer stem cells and "normal" breast cancer cells to either single or multiple doses of radiation. More of the stem cells, also called cancer-initiating cells, lived through the radiation than did the other breast cancer cells.
One good example, according to Pajonk: While 46 percent of the stem cells survived treatment with 2 Gray of radiation (a dose typically used for breast cancer treatment), only 20 percent of normal breast cancer cells did.
Then, the team simulated clinical treatment that is interrupted -- a challenge that Pajonk and other health-care providers face when patients don't make all their scheduled appointments due to fatigue, inconvenience or other factors. Pajonk and his colleagues suspect this reduces the effectiveness of radiation, and the study suggests they are correct.
When Pajonk's team exposed the cells to a higher dose of 3 Gray, every day for five days, then stopped the treatment before what would be considered a full round, the proportion of stem cells actually increased.
Pajonk's team speculated that this may happen because the radiation activates a signaling pathway that gives the stem cells the messages to self-renew.
How is it that these cells are resistant to radiation? "They may have something like a natural radiation protectant inside of them that prevents the radiation-induced DNA damage that normally kills the breast cancer cells," Pajonk said.
The findings are published in the Dec. 20 edition of the Journal of the National Cancer Institute.
The new study sends a clear message to cancer researchers, said Dr. Maximilian Diehn, a resident in radiation oncology and postdoctoral fellow at the Stanford University School of Medicine. He co-authored an editorial accompanying the study results. "The main take-home point is that this gives more evidence that we should be studying cancer stem cells more," he said. "Those cells have properties different than the rest of the tumor."
Eventually, he said, scientists may be able to develop new drugs that would overcome this resistance to radiation, he said.
The concept of cancer stem cells is fairly new, said Diehn and Pajonk. For five years or so, it has been increasingly the topic of discussion in breast cancer research, as well as prostate cancer, melanoma and other types of tumors.
A better understanding of cancer stem cells could go a long way toward treatment success, Diehn said. "Often, less than one percent of cancer cells in a tumor are actually cells critical for keeping the tumor alive and potentially spreading the cancer. This is the cancer stem cell," he said.
The new research should not discourage women from getting radiation therapy if it is recommended, Diehn and Pajonk agreed. "Radiation treatment is still one of the best treatments available for women with breast cancer," Diehn said. It's also important, he said, to follow the treatment schedule as recommended and not to have gaps in treatment because that could make the stem cells proliferate.
In another new study, Dutch researchers found that comparing current mammograms to previous ones is valuable and can reduce referrals for lesions that turn out not to be cancerous. The researchers asked 12 experienced radiologists to read 160 mammograms twice; in one case, they had previous mammograms to refer to and, in the other, they did not.
When they had access to the previous mammograms, their detection performance improved. Having the prior mammogram to look at reduced referrals by 44 percent for suspicious areas that turned out not to be cancerous.
The findings are published in the January issue of the journal Radiology.

SOURCES: Maximilian Diehn, M.D., Ph.D., resident in radiation oncology and postdoctoral fellow, Stanford University School of Medicine, Stanford, Calif.; Frank Pajonk, M.D., Ph.D., assistant adjunct professor of radiation oncology, University of California, Los Angeles, David Geffen School of Medicine; Dec. 20, 2006, Journal of the National Cancer Institute; January 2007, Radiology

<DL class=AbstractPlusReport><DT class=head>1: J Natl Cancer Inst. (http://javascript<b></b>:AL_get(this, 'jour', 'J Natl Cancer Inst.');) 2006 Dec 20;98(24):1777-85.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-custom-oxfordjournals_final_free.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=17179479&db=pubmed&url=http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17179479)<SCRIPT language=JavaScript1.2></SCRIPT> Links (http://javascript<b></b>:PopUpMenu2_Set(Menu17179479);)

<DD class=abstract><DL class=commcorr><DT>Comment in:<DD>J Natl Cancer Inst. 2006 Dec 20;98(24):1755-7. (http://www.ncbi.nlm.nih.gov/pubmed/17179471?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus)</DD></DL>The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation.

Phillips TM (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Phillips%20TM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), McBride WH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22McBride%20WH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Pajonk F (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pajonk%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1714, USA.
BACKGROUND: If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. METHODS: CD24(-/low)/CD44+ cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using flow cytometry. All statistical tests were two-sided. RESULTS: Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF(2Gy)] = 0.2, versus mammospheres, mean SF(2Gy) = 0.46, difference = 0.26, 95% confidence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF(2Gy) = 0.5, versus mammospheres, mean SF(2Gy) = 0.69, difference = 0.19, 95% CI = -0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). CONCLUSIONS: Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These findings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy.
PMID: 17179479 [PubMed - indexed for MEDLINE]
</DD></DL>1: J Cell Biochem. (javascript:AL_get(this, 'jour', 'J Cell Biochem.');) 2009 Jul 21. [Epub ahead of print]
<DD class=abstract>
Radiation responses of cancer stem cells.

Vlashi E (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Vlashi%20E%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), McBride WH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22McBride%20WH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Pajonk F (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pajonk%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc.
PMID: 19623582 [PubMed - as supplied by publisher]
</DD>

Rich66

06-05-2009, 09:21 PM

Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits? Ciara S. O’Brien<sup>1</sup>, Sacha J. Howell<sup>1</sup>, Gillian Farnie<sup>1</sup> and Robert B. Clarke<sup>1 http://www.springerlink.com/content/666n434266244635/contact.gif (http://www.springerlink.com/content/666n434266244635/fulltext.html#ContactOfAuthor4)</sup>
<table> <tbody> <tr valign="top"> <td>(1) </td> <td>Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK</td> </tr> </tbody> </table>
<table class="Contact"> <tbody> <tr> <td valign="top">http://www.springerlink.com/content/666n434266244635/contact.gif</td> <td>Robert B. Clarke
Email: robert.clarke@manchester.ac.uk</td> </tr> </tbody> </table> Received: 16 December 2008 Accepted: 10 February 2009 Published online: 28 February 2009
Abstract From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

Full article:
http://www.springerlink.com/content/666n434266244635/fulltext.html

Rich66

06-05-2009, 11:12 PM

<dl class="AbstractPlusReport"><dt class="head">1: Cell Adh Migr. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cell%20Adh% 20Migr.%27%29;) 2009 Jul 7;3(3). [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.landesbioscience.com-icon-pubmed-Landesbioscience2.jpg (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=4056&itool=AbstractPlus-def&uid=19483471&db=pubmed&url=http://www.landesbioscience.com/journals/cam/abstract.php?id=8689) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu19483471%29;)
</dt><dd class="abstract"> L1 cell adhesion molecules as regulators of tumor cell invasiveness.

Siesser PF (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Siesser%20PF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Maness PF (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Maness%20PF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
Fast growing malignant cancers represent a major therapeutic challenge. Basic cancer research has concentrated efforts to determine the mechanisms underlying cancer initiation and progression and reveal candidate targets for future therapeutic treatment of cancer patients. With known roles in fundamental processes required for proper development and function of the nervous system, L1-CAMs have been recently identified as key players in cancer biology. In particular L1 has been implicated in cancer invasiveness and metastasis, and has been pursued as a powerful prognostic factor, indicating poor outcome for patients. Interestingly, L1 has been shown to be important for the survival of cancer stem cells, which are thought to be the source of cancer recurrence. The newly recognized roles for L1CAMs in cancer prompt a search for alternative therapeutic approaches. Despite the promising advances in cancer basic research, a better understanding of the molecular mechanisms dictating L1-mediated signaling is needed for the development of effective therapeutic treatment for cancer patients.
PMID: 19483471</dd></dl>
<dl class="AbstractPlusReport"><dt class="head">1: Breast Cancer Res Treat. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res%20Treat.%27%29;) 2009 Jul 11. [Epub ahead of print]
</dt><dd class="abstract"> Antimitotic chemotherapeutics promote adhesive responses in detached and circulating tumor cells.

Balzer EM (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Balzer%20EM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Whipple RA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Whipple%20RA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Cho EH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cho%20EH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Matrone MA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Matrone%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Martin SS (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Martin%20SS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Program in Molecular Medicine, University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA.
In the clinical treatment of breast cancer, antimitotic cytotoxic agents are one of the most commonly employed chemotherapies, owing largely to their antiproliferative effects on the growth and survival of adherent cells in studies that model primary tumor growth. Importantly, the manner in which these chemotherapeutics impact the metastatic process remains unclear. Furthermore, since dissemination of tumor cells through the systemic circulation and lymphatics necessitates periods of detached survival, it is equally important to consider how circulating tumor cells respond to such compounds. To address this question, we exposed both nontumorigenic and tumor-derived epithelial cell lines to two antitumor compounds, jasplakinolide and paclitaxel (Taxol), in a series of attached and detached states. We report here that jasplakinolide promoted the extension of microtubule-based projections and microtentacle protrusions in adherent and suspended cells, respectively. These protrusions were specifically enriched by upregulation of a stable post-translationally modified form of alpha-tubulin, and this occurred prior to, and independently of any reductions in cellular viability. Microtubule stabilization with Taxol significantly enhanced these effects. Additionally, Taxol promoted the attachment and spreading of suspended tumor cell populations on extracellular matrix. While the antiproliferative effects of these compounds are well recognized and clinically valuable, our findings that microfilament and microtubule binding chemotherapeutics rapidly increase the mechanisms that promote endothelial adhesion of circulating tumor cells warrant caution to avoid inadvertently enhancing metastatic potential, while targeting cell division.
PMID: 19593636 [PubMed - as supplied by publisher]</dd></dl>

Rich66

06-09-2009, 02:50 PM

Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits? Ciara S. O’Brien1, Sacha J. Howell1, Gillian Farnie1 and Robert B. Clarke1 http://www.springerlink.com/content/666n434266244635/contact.gif (http://www.springerlink.com/content/666n434266244635/fulltext.html#ContactOfAuthor4)
(1) Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK
http://www.springerlink.com/content/666n434266244635/contact.gif Robert B. Clarke
Email: robert.clarke@manchester.ac.uk Received: 16 December 2008 Accepted: 10 February 2009 Published online: 28 February 2009
Abstract From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

Full article:
http://www.springerlink.com/content/.../fulltext.html (http://www.springerlink.com/content/666n434266244635/fulltext.html)

Lani

06-10-2009, 01:26 AM

is a gamma secretase inhibitor which interferes with the notch pathway, which is felt to be essential for cancer stem cells.

Dr. Max Wicha has been talking about using gamma secretase inhibitors as cancer stem cell specific drugs for years--this particular one has been studied quite a while as it has been under development against Alzheimer's

Rich sounds like you have now discovered the cancer stem cell literature. I urge you to read Dr. Wicha's publications and listen/look at his talks at AACR, ASCO, etc (many are online). He GETS it. I was present for that Barsky talk at the AACR in 2008--it was a precedent-setting talk, but got no coverage and most oncologists and cancer researchers never heard its results.

I recently spoke with a friend whose husband had two stem cell transplants for lymphoma (lasting 12+ years) who suddenly died of lung cancer (donor was same sex, but they were looking into other genetic tell-tale signs of
the lung cancer being "donated" along with the stem cells.

Dr. Wicha thinks radiation therapy may make things worse rather than better.

I encourage you to seek out his contributions.

Rich66

06-10-2009, 10:14 AM

Patents (1426 Stem Cell Patents)

Latest (http://www.stemcellpatents.com/patents.php) | Patents List (http://www.stemcellpatents.com/patents-list.php) | Classes (http://www.stemcellpatents.com/patents-categories.php)
http://www.stemcellpatents.com/images/icons/feed_rss_16.gif (http://www.stemcellpatents.com/feeds-stem-cell-patents.xml)

Isolation and use of solid tumor stem cells

Patent Number: 7,115,360

Date of First Priority Issue: Thursday August 3rd, 2000
Date Issued: Tuesday October 3rd, 2006
Assignee: Regents of the University of Michigan (Ann Arbor, MI)
Inventors: Clarke; Michael F. (Ann Arbor, MI), Morrison; Sean J. (Ann Arbor, MI), Wicha; Max S. (Ann Arbor, MI), al-Hajj; Muhammad (La Jolla, CA)

From Class: Type (http://www.stemcellpatents.com/patents-categories-show-6)
Comments: No comments (http://www.stemcellpatents.com/patents-show-1032#comments)

The cancer stem cell is very important since there is numerous investigators in the field that believe the majority of cancer cells making up a tumor mass are only the products of a specific cell subpopulation with high repopulating potential. What this means is that usually the drugs developed for cancer are developed to kill not the stem cell of the tumor, but actually the progeny of the tumor stem cell. This means (if the theory is correct) that the majority of cancer treatments are bound to fail since they do not address the cell subpopulation that maintains to other tumor cells.

This patent covers methods of detecting compounds that are capable of killing the cancer stem cell.

The patent is focus on cancer stem cells from epithelial tumors that have the phenotype of CD44+ and lineage negative. Specific lineage markers that are not found on cancer stem cells include CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b: according to this patent.

View this patent on the USPTO website (http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7,115,360.PN.&OS=PN/7,115,360&RS=PN/7,115,360).

Rich66

06-10-2009, 10:18 AM

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Cancer Stem Cell Theory Heads to the Clinic

[Article]
Tuma, Rabiya S. PhD

The idea that cancer stem cells drive tumor growth and recurrence has been gaining momentum in recent years, as researchers expand the list of malignancies that appear to harbor such cell populations.
Yet clear evidence that cancer stem cells are important in human disease is lacking. Now, several researchers have recently launched clinical trials, or plan to do so in the next few months, that will test the importance of these cells in human cancer.
I fully believe that there are stem cells in almost every cancer but one of the interesting things is that there has never been any clinically derived benefit from any of those findings, said William Matsui, MD, Assistant Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, who identified a putative stem cell population in multiple myeloma.
Hypothesis

According to the stem cell hypothesis, cancers have a small group of cells that are uniquely responsible for repopulating the tumor. The bulk of the tumor, in contrast, is made up of differentiated or partially differentiated cells that cause symptoms and physiological problems for the patient but that cannot reestablish a tumor when transplanted to an immune-compromised mouse.
<table class="ptDocfigure"> <tbody><tr> <td class="ptDocImages">http://www.oncology-times.com/pt/ServeImage;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cwhh4c 2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195629% 218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU1&type=thumb (http://javascript%3Cb%3E%3C/b%3E:newWindow%28%27/pt/re/oncotimes/popUpImage.htm;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cw hh4c2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195 629%218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU1&type=full%27,%27FFU1%27,%27width=550,height=500,lo cation=yes,toolbar=yes,status=yes,menubar=yes,scro llbars=yes,resizable=yes%27%29)</td><td class="ptDocCaption"> Figure. William Matsui, MD: I fully believe that there are stem cells in almost every cancer but one of the interesting things is that there has never been any clinically derived benefit from any of those findings.
</td> </tr> </tbody></table>
For example, when Michael Clarke, MD, Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine, was still at the University of Michigan, his team showed that as few as 100 breast tumor cells that carried particular cell surface markers (CD44 positive and CD24 negative or low), could give rise to a new tumor when injected into a mouse, while injection of more than 20,000 of the tumor cells that lack these cell surface markers did not.
Moreover, when the newly formed tumors were examined, they looked much like the original human tumor, containing few of the CD44+CD24-/low stem cells and the majority of the cells looking more differentiated.
The hypothesis for now suggests that a specific cell population from a given tumor type are the crux of the problem from the beginning of a disease to a patient's death. That is probably overly simplified, Dr. Matsui said.
For example, the stem cells are likely to change over the course of the disease even while they remain critical for disease progression. Like any new theory we tend to oversimplify it, but it does give us a kind of framework to sit down with and imagine how and when relapse would occur, he said. Our job now is to show that they are somehow clinically relevant.
Finding the Right Targets

There is growing evidence that the stem cell populations in various malignancies are resistant to standard therapies that reduce the bulk of the tumor. For example, Dr. Matsui and colleagues found that bortezomib and lenalidomide kill myeloma plasma cells but not the stem cells that produce the plasma cells. Thus, if the stem cell hypothesis is correct, new therapies that kill these cells need to be identified.
<table class="ptDocfigure"> <tbody><tr> <td class="ptDocImages">http://www.oncology-times.com/pt/ServeImage;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cwhh4c 2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195629% 218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU2&type=thumb (http://javascript%3Cb%3E%3C/b%3E:newWindow%28%27/pt/re/oncotimes/popUpImage.htm;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cw hh4c2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195 629%218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU2&type=full%27,%27FFU2%27,%27width=550,height=500,lo cation=yes,toolbar=yes,status=yes,menubar=yes,scro llbars=yes,resizable=yes%27%29)</td><td class="ptDocCaption"> Figure. Craig Jordan, PhD: There is a convergence of two fields. Over the last several decades cancer biologists have identified key pathways in cancer cell growth, and now researchers are testing whether those same pathways are relevant to the stem cells.…By bringing the two fields together we are going to leapfrog some of the drug-development process.
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For example, Duke University researchers reported earlier this year that glioblastoma stem cells, which carry the CD133 cell surface marker, are less susceptible to radiation damage than are the other cells in the tumor.
Upon closer examination the researchers discovered that all of the cancer cells sustained a similar amount of DNA damage from the radiation, but that the stem cells had better repair mechanisms. When activation of cell cycle checkpoints was blocked, the irradiated stem cells died.
Convergence of Two Fields

There is a convergence of two fields here, explained Craig Jordan, PhD, Associate Professor of Medicine at the University of Rochester School of Medicine. Over the last several decades cancer biologists have identified key pathways in cancer cell growth; and now researchers in the cancer stem cell field are testing whether those same pathways are relevant to the stem cells.
Fortuitously a lot of those key cancer pathways are probably also important in stem cells. So by bringing the two fields together we are going to leapfrog some of the drug-development process, rather than having to start at the beginning again, he said.
One approach to targeting the stem cells is to hit some of the cell surface markers that appear on multiple malignancies. For example, CD44 appears on stem cells from breast, head and neck, and pancreatic tumor cells, while CD20 characterizes multiple myeloma and melanoma stem cells. Thus some therapies may be effective in multiple malignancies.
It remains to be proven, but my prediction is that that is exactly what will happen, said Max Wicha, MD, Professor of Internal Medicine and Director of the University of Michigan Comprehensive Cancer Center.
Significantly, some of the cell surface markers that characterize cancer stem cells have already been targeted with successful drugs. For example, rituximab, ibritumomab tiuxetan (Zevalin), and iodine-131 tositumomab (Bexxar), which are approved for the treatment of non-Hodgkin's lymphoma, target the CD20 antigen.
It may be that drugs like Bexxar will have some efficacy in treating the stem cells in melanoma, for which we don't have very good therapies, so this is really very exciting, Dr. Wicha said.
The catch to targeting markers shared by several different cancer stem cells is that they might also be present on normal stem cells, either in the tissue where the malignancy forms or elsewhere in the body. I think part of the challenge of stem cell based therapies is trying to figure out what we can do without completely kiboshing every stem cell in the body, Dr. Matsui said.
CD44 is a case in point. As reported earlier this year, CD44 is involved in engraftment of leukemic stem cells and may aid metastasis in other diseases. Therefore blocking the cell surface marker could be a valuable weapon in disease control, if it is not too toxic for a variety of healthy stem cells that also carry the marker.
CD44 is expressed on normal stem cells, so I would be worried about a magic bullet-sort of strategy. It may be unnecessarily toxic, said Richard Van Etten, MD, PhD, Professor of Medicine at Tufts-New England Medical Center.
That doesn't completely rule out the use of such antibodies, though. For example, the CD44 cell surface marker is expressed on the putative stem cells in chronic myelogenous leukemia (CML). Imatinib induces rapid responses, but patients relapse if they go off the drug, suggesting that the stem cells escape the drug's effects, an observation supported by in vitro data.
Dr. Van Etten said that if the field goes back to using autologous transplantation to treat these patients, their harvested cells could be treated with a CD44 antibody in vitro, prior to reintroduction. Because CML stem cells rely on the CD44 cell surface protein for engraftment in a way that healthy stem cells do not, the pretreatment could prevent relapses down the line.
Clinical Trials Moving Forward

Despite the challenges, several trials are in the works-either already enrolling patients or in the final design stages-including three trials testing anti-CD20 antibody therapies in multiple myeloma.
The drugs do not affect the mature plasma cells that comprise most of the neoplastic cells, which lack the CD20 antigen, so all of the trials require that the patients undergo some debulking therapy as well.
* In a Phase II trial at the University of Michigan Comprehensive Cancer Center, Andrzej Jakubowiak, MD, PhD, Director of the Multiple Myeloma Center, is testing iodine-131 tositumomab as a consolidation therapy in patients with Stage II or III disease who have had at least a partial response to standard therapies. The research team will follow patients' progress with serial bone marrow biopsies.
* At the Sidney Kimmel Cancer Center at Johns Hopkins, Carol Ann Huff, MD, a multiple myeloma specialist, and Dr. Matsui are combining the use of cyclophosphamide and rituximab in a Phase II trial.
<table class="ptDocfigure"> <tbody><tr> <td class="ptDocImages">http://www.oncology-times.com/pt/ServeImage;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cwhh4c 2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195629% 218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU3&type=thumb (http://javascript%3Cb%3E%3C/b%3E:newWindow%28%27/pt/re/oncotimes/popUpImage.htm;jsessionid=KvqMb0VTJSbRzbMm2yLJ44Cw hh4c2gQlY9y222Xv6Gm02vQpdZkF%211966694724%21181195 629%218091%21-1%211244654157000?an=00130989-200705100-00011&id=FFU3&type=full%27,%27FFU3%27,%27width=550,height=500,lo cation=yes,toolbar=yes,status=yes,menubar=yes,scro llbars=yes,resizable=yes%27%29)</td><td class="ptDocCaption"> Figure. Max S. Wicha, MD, is planning the first trial to test the stem cell hypothesis in a solid cancer. The trial will be run at three centers-the University of Michigan, Dana-Farber, and Baylor-and will test an inhibitor of the Notch signaling pathway, which is active in most stem cells.
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Patients with relapsed or refractory disease receive two doses of the antibody followed by the standard high-dose cyclophosphamide regimen. Following the chemotherapy, patients receive four weekly doses of the antibody, and three subsequent doses at three-month intervals. As with the Michigan protocol, patient progress is being followed via repeated bone marrow biopsies.
So far, about half of the approximately 40 patients planned for the trial have been treated. It is too early to say whether the anti-CD20 antibody is having an effect, but the team expects some good correlative data within the next year, Dr. Matsui said. What we are after is proof of principle-in other words, can the team show that cancer stem cells exist in human disease and have a clinical role in progression?
* In an ongoing trial at Tufts-New England Medical Center, Andreas Klein, MD, Clinical Director of Lymphoma and Myeloma Services, is testing the ability of yttrium-90 ibritumomab tiuxetan to improve the clinical outcomes of myeloma patients undergoing autologous stem cell transplants.
Patients who have an incomplete response to chemotherapy prior to transplantation receive the Zevalin according to the standard dosing protocol, and progress is assessed after four and 10 weeks, after which the patients proceed to standard autologous transplant.
* Several other teams are working on trials in leukemia, though they are using different molecular targets to hit the stem cells. Dr. Jordan's group in Rochester found that parthenolide, which is the main compound in the herbal remedy feverfew, is toxic to both the stem cells and the differentiated leukemic cells. The researchers have developed a derivative of the agent that has better pharmacologic properties and expect to start a Phase I trial sometime this summer.
Preclinical data indicate that the drug has broad activity in hematologic malignancies, so the enrollment criteria will not be limited to one type of leukemia. Our drug seems to have limited toxicity in preclinical studies, Dr. Jordan. It seems to target a step in leukemia molecular biology that is relatively unique to those cells and not particularly relevant to healthy cells or normal stem cells.
* Stemline Therapeutics, Inc. in New York City has an ongoing trial testing the drug SL-401, which targets the interleukin-3 receptor (IL-3R, also called CD123) on leukemia stem cells. Thirty patients are enrolled thus far, and the maximally tolerated dose of the drug has not been reached, said Ivan Bergstein, MD, the company's Chairman and CEO.
We are seeing activity at these doses, with very few side effects, he added. We've basically gotten our green light in terms of gearing up for Phase II trials, but we may end up having a higher dose than we currently have used. The IL-3R is expressed at a higher level on leukemic stem cells than on healthy ones, so the group expects there to be a nice therapeutic window, he said.
When asked why the company chose to venture into the realm of stem cell-targeted therapy before the clinical importance of cancer stem cells has been proven, Dr. Bergstein pointed to the expanding body of preclinical and laboratory data to support the notion. He also notes, however, that the IL-3R protein exists on all of the leukemic cells, not just the stem cells-so the drug's success is not entirely based on the accuracy of the stem cell hypothesis.
* Meanwhile, Dianna Howard, MD, of the University of Kentucky Markey Cancer Center, is testing the combination of two established drugs in acute myeloid leukemia (AML) patients. In vitro work shows that combined bortezomib and idarubicin kills differentiated AML cells as well as the less-differentiated cancer stem cells.
The trial is already recruiting patients over age 60 with newly diagnosed disease or patients over the age of 18 with relapsed or refractory disease. The primary endpoint is to establish the safety and maximally tolerated doses for the regimen. The secondary endpoints include clinical response and bortezomib-induced inhibition of the NF-kappa B signaling pathway, which is active in leukemic stem cells.
* Similarly, Doug Smith, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins, and colleagues at other centers are testing imatinib in combination with both new and old therapies. Unlike patient responses to imatinib, which are frequent and rapid, only a fraction of patients respond to interferon, and the full response can take years.
However, when patients are taken off the drug, they appear, based on long-term follow-up data, to be free of disease, suggesting that the drug kills the stem cells. Dr. Smith is therefore combining imatinib, interferon, and granulocyte macrophage colony-stimulating factor (GM-CSF), which appears to speed interferon response, in one arm of a randomized Phase II trial. The second arm combines imatinib with the whole cell vaccine K562 and GM-CSF.
We don't know which is better yet, the vaccine or interferon, says Dr. Matsui, who is involved with the trial. The multicenter trial aims to recruit about 56 patients with chronic-phase CML, and to examine the rate of molecular remission and toxicity of the regimens.
* Finally, Dr. Wicha is putting together the first trial to test the stem cell hypothesis in a solid cancer. The trial will be run at three centers including the University of Michigan, Dana-Farber Cancer Center, and Baylor College of Medicine, and will test an inhibitor of the Notch signaling pathway, which is active in most stem cells.
Dr. Wicha said he is not ready to disclose which Notch inhibitor the group will be using, other than to say that it is from a big pharmaceutical company and that the company will be involved with the trial.
'A Healthy Degree of Skepticism'

One key issue facing the clinical researchers is how to define success when evaluating a potential stem cell therapy.
Standard tumor regression assessments, such as Response Evaluation Criteria in Solid Tumors (RECIST), are not appropriate for these therapies. The ideal response criteria would be an improvement overall in survival, but that will take too long to be of practical use. Correlative laboratory data will help bolster the case, but is not typically adequate for regulatory approval.
To tackle this question, the NCI plans to hold a meeting in January, but for now, cancer stem cell pioneer Max S. Wicha, MD, Director of the University of Michigan Comprehensive Cancer Center, said he remains optimistic that the proper trial designs can be found and that the problem is a passing one.
It will only be a problem until some group proves that patients live longer on these therapies. As soon as that happens, I think everybody will jump into this. Until that happens I think one should have a healthy degree of skepticism because it remains a theory. We think it is a promising theory, but until you can actually prove that it makes a difference for patients, you have to say it remains a theory.
These Cancers Appear to Have Stem Cells

Brain
Breast
Colon
Head and Neck
Ovary
Liver
Prostate
Pancreas
Leukemias
Myeloma
Melanoma
Sarcomas

© 2007 Lippincott Williams & Wilkins, Inc.

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Rich66

06-10-2009, 10:45 AM

Journal of Clinical Oncology, Vol 26, No 17 (June 10), 2008: pp. 2795-2799
© 2008 American Society of Clinical Oncology. (http://jco.ascopubs.org/misc/terms.dtl)
DOI: 10.1200/JCO.2008.17.7436

Cancer Stem Cells: A Step Toward the Cure

<nobr>Bruce M. Boman</nobr> Helen F. Graham Cancer Center, Newark, DE; Thomas Jefferson University, Philadelphia, PA
<nobr>Max S. Wicha</nobr>
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
This special issue of Journal of Clinical Oncology is devoted<sup> </sup>to the emerging field of cancer stem cells (CSCs). The goal<sup> </sup>of this article is to introduce general concepts of CSC biology<sup> </sup>to clinicians, and to provide a framework for their understanding<sup> </sup>the CSC-based approach to the development of novel diagnostics,<sup> </sup>therapeutics, and prevention strategies in oncology.

5 page article with PDF:

http://jco.ascopubs.org/cgi/content/full/26/17/2795

Rich66

06-11-2009, 02:24 PM

<dl class="AbstractPlusReport"><dt class="head">1: Clin Cancer Res. (javascript:AL_get(this, 'jour', 'Clin Cancer Res.');) 2009 Jun 9. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-clincanres_full.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=19509181&db=pubmed&url=http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509181)
</dt><dd class="abstract"> Association of Breast Cancer Stem Cells Identified by Aldehyde Dehydrogenase 1 Expression with Resistance to Sequential Paclitaxel and Epirubicin-Based Chemotherapy for Breast Cancers.

Tanei T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanei%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Morimoto K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Morimoto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Shimazu K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shimazu%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kim SJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kim%20SJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tanji Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanji%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Taguchi T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Taguchi%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tamaki Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tamaki%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Noguchi S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Noguchi%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Authors' Affiliation: Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
PURPOSE: Breast cancer stem cells have been shown to be associated with resistance to chemotherapy in vitro, but their clinical significance remains to be clarified. The aim of this study was to investigate whether cancer stem cells were clinically significant for resistance to chemotherapy in human breast cancers.EXPERIMENTAL DESIGN: Primary breast cancer patients (n = 108) treated with neoadjuvant chemotherapy consisting of sequential paclitaxel and epirubicin-based chemotherapy were included in the study. Breast cancer stem cells were identified by immunohistochemical staining of CD44/CD24 and aldehyde dehydrogenase 1 (ALDH1) in tumor tissues obtained before and after neoadjuvant chemotherapy. CD44(+)/CD24(-) tumor cells or ALDH1-positive tumor cells were considered stem cells.RESULTS: Thirty (27.8%) patients achieved pathologic complete response (pCR). ALDH1-positive tumors were significantly associated with a low pCR rate (9.5% versus 32.2%; P = 0.037), but there was no significant association between CD44(+)/CD24(-) tumor cell proportions and pCR rates. Changes in the proportion of CD44(+)/CD24(-) or ALDH1-positive tumor cells before and after neoadjuvant chemotherapy were studied in 78 patients who did not achieve pCR. The proportion of ALDH1-positive tumor cells increased significantly (P < 0.001) after neoadjuvant chemotherapy, but that of CD44(+)/CD24(-) tumor cells did not.CONCLUSIONS: Our findings suggest that breast cancer stem cells identified as ALDH1-positive, but not CD44(+)/CD24(-), play a significant role in resistance to chemotherapy. ALDH1-positive thus seems to be a more significantly predictive marker than CD44(+)/CD24(-) for the identification of breast cancer stem cells in terms of resistance to chemotherapy.
PMID: 19509181 [PubMed - as supplied by publisher]
</dd></dl>

Rich66

06-13-2009, 12:53 PM

A blog that tracks this issue;
http://cancerstemcellnews.blogspot.com/

Rich66

06-13-2009, 01:51 PM

Company working on prostate cancer treatment has explanation of CSCs with strong parallels to BC:

http://www.pro-curetherapeutics.com/cancer_stem_cells.asp

Rich66

06-13-2009, 05:10 PM

Interview with Max Wicha which includes reference to Repertaxin as well as discussion of Her2 connection to cancer stem cells.

Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha CME

Published: 01/20/2009<table id="articletoolbox" border="0" cellpadding="0" cellspacing="0"><tbody><tr valign="top"><td id="articletoolboxborder">

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 Editor's Note:
Increasing evidence suggests that breast cancers might be targets of transformation during carcinogenesis and that deregulation of self-renewal carried out by stem cells might be one of the key events involved in breast carcinogenesis. The understanding of the molecular pathways underlying these changes is increasing; these alterations are now known to involve pathways such as Hedgehog and Notch, which may represent novel targets of breast cancer development and recurrence. Studies are also identifying markers of stem cells, which may help further characterize the basal, luminal, and other subtypes of breast cancer. At the 31st Annual San Antonio Breast Cancer Symposium (SABCS), several presentations focused on breast cancer stem cells. Research in this area is just beginning and ultimately may help inform clinical practice and enable the development of novel treatment approaches. Medscape Oncology recently spoke about these advances with Max S. Wicha, MD, Distinguished Professor of Oncology at the University of Michigan, Ann Arbor. Dr. Wicha is principal investigator for some of the seminal studies in this area.
Medscape: What is the current thinking on the role of stem cells in the pathology and treatment of breast cancer?
Dr. Wicha: We have been interested in the concept that cancers are driven by a small component of cells that have stem cell properties and that targeting these cells may result in improved outcomes for patients with cancer. Our laboratory was the first to identify a small population of cells with stem cell properties in human breast cancers, and we found that these cells could be prospectively identified with use of cell surface markers.<sup>[1] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> Properties of these stem cells include the ability to be serially transplanted into immunosuppressed mice, as well as the ability to reproduce the heterogeneity of cells found in the initial tumor.
Research involving cell cultures and animal models has demonstrated that cancer stem cells are relatively resistant to chemotherapy and radiation therapy.<sup>[2,3] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> Recent clinical studies have supported this concept, including one study of neoadjuvant chemotherapy that demonstrated that the proportion of cells with stem cell markers increases after neoadjuvant chemotherapy.<sup>[4] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> In this neoadjuvant therapy study, women whose tumors overexpressed HER-2 had a higher number of stem cells than those with tumors that did not overexpress this gene. Furthermore, in contrast with chemotherapy, addition of the HER-2 inhibitor lapatinib recently has been found to reduce the proportion of breast cancer stem cells present following neoadjuvant therapy.<sup>[5] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> These results may be explained by our laboratory's recent findings that HER-2 is an important regulator of breast cancer stem cells and that HER-2 inhibitors such as trastuzumab or lapatinib are able to selectively target cancer stem cells.<sup>[6] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup>
One of the biggest challenges we now face in breast cancer treatment is to develop more effective therapies that are able to target the breast cancer stem cell population. At the 2008 SABCS, I presented data showing that breast cancer stem cells are regulated by the tumor microenvironment.<sup>[7] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> Specifically, our group demonstrated that mesenchymal stem cells, which we believe originate in the bone marrow and "traffic" into tumors, are able to regulate breast cancer stem cells. The feedback loops between mesenchymal stem cells and breast cancer stem cells provide new targets for therapies aimed at eliminating the cancer stem cell population. We also found that when breast cancers are treated with chemotherapy, the dying cancer cells secrete the chemokine interleukin (IL)-8. This occurs as part of a normal damage response. However, IL-8 is able to stimulate cancer stem cells through the CXCR1 chemokine receptor. The interaction between dying cancer cells producing IL-8 and CXCR1 stimulation of cancer stem cells contributes to the increase in cancer stem cells following chemotherapy. In mouse models we have shown that we can block these pathways with use of an antibody or a small molecule inhibitor to the CXCR1 receptor and can thus directly target and reduce the cancer stem cell population.
Medscape: Would blocking the CXCR1 receptor be expected to reduce recurrence?
Dr. Wicha: Yes, that is our hypothesis -- that targeting cancer stem cells through the CXCR1 receptor would reduce recurrence, which may be driven by chemotherapy-resistant cancer stem cells. This is consistent with our findings in mouse models.
Medscape: What agents did you use against IL-8 or CXCR1 in your studies?
Dr. Wicha: We used antibodies against IL-8 or a small molecule inhibitor of CXCR1 called repertaxin. Repertaxin was developed as an anti-inflammatory agent to be used to prevent heart damage after myocardial infarction. Repertaxin has been tested in phase 1 clinical trials. Our studies indicate that this approach may provide a strategy to selectively target breast cancer stem cells.
Medscape: What other pathways might be involved in mediating stem cell signaling?
Dr. Wicha: It is becoming clear that a number of other signaling pathways regulate cancer stem cells. One important pathway is the Notch pathway. Small molecules, such as gamma secretase inhibitors, are able to inhibit Notch signaling; in mouse models, this Notch inhibitor has been shown to reduce the population of cancer stem cells. On the basis of this concept, phase 1 clinical trials that utilize gamma secretase inhibitors are now in progress at our cancer center as well as others. We are also trying to combine Notch inhibitors with cytotoxic chemotherapy such as docetaxel, inasmuch as our preclinical findings suggest that these signaling agents may sensitize cancer stem cells to chemotherapy.
The Hedgehog pathway may also regulate stem cells. The ligands for Hedgehog may act on cells in the tumor stroma, and the interaction between the stroma and breast cancer stem cells may regulate their growth. Small molecule Hedgehog inhibitors have now been tested in phase 1 clinical trials and are about to enter phase 2 trials for breast cancer. In light of recent studies<sup>[8,9] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> that have confirmed an important role for cytokine signaling in the regulation of breast cancer stem cells, future approaches may combine agents that can inhibit stromal cell signaling with stem cell inhibitors such as Notch and Hedgehog.
Recent studies suggest that characteristics of molecular subcategories of breast cancer may be driven by stem cells that can be identified with different markers.<sup>[10,11] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> These differences may result from the origin of breast cancers -- whether stem or progenitor cells -- or different mutations that drive the various molecular subtypes. Ultimately, molecular analysis of breast cancer self-renewal pathways may allow for the individualization of therapy designed to target these different stem cell populations.
Medscape: What were some other important findings related to breast cancer stem cells presented at SABCS this year?
Dr. Wicha: A study by Atkas and colleagues demonstrated that cancer cells that express stem cell markers could be isolated from circulating blood in 28 patients with metastatic breast cancer.<sup>[12] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> Furthermore, they showed that these cells expressed not only the stem cell marker aldehyde dehydrogenase (ALDH)-1 but also markers of epithelial-mesenchymal transition (EMT), a phenotypic change that may allow cells to travel to the site of metastasis formation while avoiding elimination by standard treatment. Markers of EMT that have been investigated include Twist, Akt2, and PI3K. Samples were also investigated separately for the stem cell marker ALDH-1. Circulating tumor cells (CTCs) were detected in 12 of 28 (43%) breast cancer samples. In the samples that were positive for CTCs, 50% were positive for at least one EMT marker and 42% were positive for ALDH-1. In the group that was negative for CTCs, only 19% and 12% expressed EMT markers or ALDH-1, respectively. These studies suggest that cancer stem cells can display an EMT phenotype and that these cells are relatively resistant to chemotherapy and can be detected in the circulation.
Medscape: What are some of the important stem cell markers currently under investigation?
Dr. Wicha: Our laboratory was the first to show that expression of the enzyme ALDH is a useful marker for normal and malignant breast stem cells.<sup>[13] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> ALDH also can be used to isolate breast cancer stem cells from human tissue. Jolicoeur and colleagues found that ALDH tends to be expressed on basal-type rather than luminal-type breast cancers.<sup>[14] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> These researchers studied formalin-fixed, paraffin-embedded specimens from 57 patients with breast cancer. The samples were assessed with immunohistochemistry for ALDH-1 as well as the estrogen and progesterone receptors (ER and PR, respectively) and HER-2. Basal cell markers investigated included epidermal growth factor receptor (EGFR)-1, CK5, CK14, CK17, and smooth muscle alpha-actin (SMA); luminal cell markers included CK19 and epithelial membrane antigen (EMA).
These investigators found that breast cancer specimens that were triple negative (ie, negative for ER, PR, and HER-2) and also expressed at least one basal cell marker were more likely to be positive for ALDH-1 staining. These findings suggest that basal cancers may arise from primitive mammary stem cells. At least some of the luminal cancers (which have a more favorable prognosis) are not as likely to express ALDH. These findings support the concept that different molecular subcategories of breast cancer may be derived from different cells and may express distinct markers.
Other markers that have been used to identify breast cancer stem cells include CD44 positivity and CD24 negativity.<sup>[1] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> It has been relatively difficult to identify these markers using immunohistochemistry. According to study findings presented at SABCS, however, Rimm and colleagues used the fluorescent AQUA [automated quantitative analysis] technique<sup>[15] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> to combine ALDH staining with CD44 expression and demonstrated that ALDH-positive CD44 cells correlated with a poor prognosis. On the basis of their findings, they suggest that combining ALDH and CD44 may be superior to use of either marker alone for the detection of breast cancer stem cells.
Medscape: What are some other important issues with respect to stem cells in breast cancer?
Dr. Wicha: A study by Latimer and colleagues suggests that racial differences in breast carcinogenesis may relate in part to the differences in the ability of breast stem cells to differentiate in white vs African-American women.<sup>[16] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> African-American women are more likely to die from breast cancer, and the incidence of breast cancer is higher in African-American women under 40 years of age compared with white women of the same age. With use of a mammary tissue module, these researchers found that race was a modifying factor in the ability of cells to form ductal structures in vitro, which significantly increased the rate of differentiation. They suggest that if breast tissue from African-American women has a more robust differentiation potential than that of white women, it may also contain more stem cells, associated with an aggressive tumor type. In addition, our group has found different frequencies of ALDH positivity in African-American women compared with white populations. Together, these studies may provide a partial explanation for the increased incidence of breast cancer in African-American women.
Medscape: Do you think that the key stem cell markers have been identified, or do several stem cell markers remain to be found?
Dr. Wicha: The field of cancer stem cell research is in its early stages. It is going to be very important to search for more stem cell markers, particularly for luminal breast cancers. We currently have effective markers for identifying stem cells in basal breast cancers, but it is becoming clear that luminal breast cancers may be driven by different stem cells.
Another important question exists regarding the relationship of HER-2 expression and cancer stem cells. Our laboratory has recently shown that HER-2 overexpression increases cancer stem cell frequency. This finding is also consistent with our clinical data that show an increase in ALDH-positive cells in HER-2-positive breast cancers. The remarkable efficacy of agents such as trastuzumab and lapatinib in treating metastatic and early-stage breast cancer may relate to the fact that these agents are able to target breast cancer stem cells. Mechanisms of trastuzumab resistance as well as the question of whether trastuzumab can benefit women without HER-2-amplified tumors are open questions that need further investigation.
Medscape: How far away is the application of these findings in clinical practice?
Dr. Wicha: Cancer stem cell research is still in its infancy. However, use of stem cell inhibitors such as gamma secretase inhibitors to inhibit Notch signaling or Hedgehog inhibitors is currently being investigated in early-phase clinical trials. Neoadjuvant trial designs such as those reported by Dr. Jenny Chang at Baylor College of Medicine in Houston, Texas, will provide important new information on the ability of these agents to specifically target breast cancer stem cells.<sup>[5] (http://javascript%3Cb%3E%3C/b%3E:newshowcontent%28%27active%27,%27references%2 7%29;)</sup> In these studies, it will also be important to measure the effect of treatment on stem cell markers as well as on the pathways that drive cancer stem cells.
This activity is supported by an independent educational grant from Susan G. Komen for the Cure.
<hr noshade="noshade"> References (http://javascript%3Cb%3E%3C/b%3E:showcontent%28%27references%27%29;)
[ CLOSE WINDOW ]
References

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988. Abstract (http://cme.medscape.com/medline/abstract/12629218)
Chen MF, Lin CT, Chen WC, et al. The sensitivity of human mesenchymal stem cells to ionizing radiation. Int J Radiat Oncol Biol Phys. 2006;66:244-253. Abstract (http://cme.medscape.com/medline/abstract/16839703)
Wicha MS. Identification of murine mammary stem cells: implications for studies of mammary development and carcinogenesis. Breast Cancer Res. 2006;8:109.
Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672-679. Abstract (http://cme.medscape.com/medline/abstract/18445819)
Chang JC, Li X, Creighton C, et al. Decrease in tumorigenic breast cancer stem cells -- final results of a neoadjuvant trial in primary breast cancer patients. Program and abstracts of the 6th European Breast Cancer Conference (EBBC); April 15-19, 2008; Berlin, Germany. Abstract 204
Korkaya H, Paulson A, Iovino F, Wicha MS. HER-2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120-6130. Abstract (http://cme.medscape.com/medline/abstract/18591932)
Wicha M. Molecular targets in breast cancer stem cells. Program and abstracts of the 31st Annual San Antonio Breast Cancer Symposium (SABCS); December 10-14, 2008; San Antonio, Texas. Basic Science Panel Discussion.
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557-563. Abstract (http://cme.medscape.com/medline/abstract/17914389)
Beider K, Abraham M, Peled A. Chemokines and chemokine receptors in stem cell circulation. Front Biosci. 2008;13:6820-6833. Abstract (http://cme.medscape.com/medline/abstract/18508696)
Dontu G. Breast cancer stem cell markers -- the rocky road to clinical applications. Breast Cancer Res. 2008;10:110.
Honeth G, Bendahl PO, RingnÃ©r M, et al. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.
Aktas B, Tewes M, Hauch S, Fehm T, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers on circulating tumor cells in patients with metastatic breast cancer. Cancer Res. 2009;69(suppl 2):84s. Abstract 107.
Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555-567.
Jolicoeur F, Garcia de la Fuente I, Gaboury L, Balicki D. ALDH1 is a useful marker of basalness in human breast cancer and its stem/progenitor cells. Cancer Res. 2009;69(suppl 2):83s. Abstract 104.
Rimm DL, Barlow WE, Harigopal M, et al. Multiplexed AQUA-based assessment of SWOG 9313 shows prognostic value of continuous ER, PR and HER-2 assessment. Cancer Res. 2009;69(suppl 2):97s.
Latimer JJ, Lalanne NA, Myers NT, Courtney AB, Mock L, Grant SG. A new paradigm for African American breast cancer involving stem cell differentiation. Cancer Res. 2009;69(suppl 2):324s. Abstract 5051.

 Contents of Highlights of SABCS 2008 (http://cme.medscape.com/viewprogram/18884) All sections of this activity are required for credit.

Highlights in HER-2-Positive Breast Cancer (http://cme.medscape.com/viewarticle/586897)
Highlights in Adjuvant Endocrine Therapy for Breast Cancer (http://cme.medscape.com/viewarticle/586899)
Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha

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Rich66

06-13-2009, 05:57 PM

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Sci. (javascript:AL_get(this,%20'jour',%20'Cancer%20Sci .');) 2009 Jun;100(6):1062-8. Epub 2009 Mar 9.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www3.interscience.wiley.com-aboutus-images-wiley_interscience_150x34.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3046&itool=AbstractPlus-def&uid=19385968&db=pubmed&url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1347-9032&date=2009&volume=100&issue=6&spage=1062) <script language="JavaScript1.2"></script>Links (javascript:PopUpMenu2_Set(Menu19385968);)
</dt><dd class="abstract"> Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression.

Morimoto K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Morimoto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kim SJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kim%20SJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tanei T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanei%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Shimazu K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shimazu%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tanji Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanji%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Taguchi T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Taguchi%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tamaki Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tamaki%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Terada N (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Terada%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Noguchi S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Noguchi%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.
Recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast cancer stem cells. The aim of our study was to investigate the clinicopathological characteristics of breast cancers with ALDH1+ cancer stem cells. In addition, the distribution of ALDH1+ tumor cells was compared on a cell-by-cell basis with that of estrogen receptor (ER)+, Ki67+, or human epidermal growth factor receptor type 2 (HER2)+ tumor cells by means of double immunohistochemical staining. Immunohistochemical staining of ALDH1 was applied to 203 primary breast cancers, and the results were compared with various clinicopathological characteristics of breast cancers including tumor size, histological grade, lymph node metastases, lymphovascular invasion, ER, progesterone receptor, HER2, Ki67, and topoisomerase 2A as well as prognosis. Immunohistochemical double staining of ALDH1 and ER, Ki67, or HER2 was also carried out to investigate their distribution. Of the 203 breast cancers, 21 (10%) were found to be ALDH1+, and these cancers were significantly more likely to be ER- (P = 0.004), progesterone receptor- (P = 0.025), HER2+ (P = 0.001), Ki67+ (P < 0.001), and topoisomerase 2A+ tumors (P = 0.012). Immunohistochemical double staining studies showed that ALDH1+ tumor cells were more likely to be ER-, Ki67-, and HER2+ tumor cells. Patients with ALDH1 (score 3+) tumors showed a tendency (P = 0.056) toward a worse prognosis than did those with ALDH1- tumors. Breast cancers with ALDH1+ cancer stem cells posses biologically aggressive phenotypes that tend to have a poor prognosis, and ALDH1+ cancer stem cells are characterized by ER-, Ki67-, and HER2+.
PMID: 19385968 [PubMed - in process
</dd></dl>

Rich66

06-15-2009, 08:19 AM

Mammary stem cell number as a determinate of breast cancer risk

http://breast-cancer-research.com/content/9/4/109

Rich66

06-16-2009, 10:04 PM

<table width="100%" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td valign="center" align="left">Web address:
http://www.sciencedaily.com/releases/2009/06/
090616103323.htm</td><td id="printbutton" valign="center" align="right"><input onclick="window.print()" value="Print this page" type="button"></td></tr></tbody></table>Cancer Researchers Develop Model That May Help Identify Cancer Stem Cells

ScienceDaily (June 15, 2009) — Researchers at UCLA's Jonsson Comprehensive Cancer Center, on a quest to find lung cancer stem cells, have developed a unique model to allow further investigation into the cells that many believe may be at the root of all lung cancers.

If researchers could find a way to isolate and grow lung cancer stem cells, they could study their biologic mechanisms and perhaps identify targets for new therapies, said Raj Batra, an associate professor of medicine and a Jonsson Cancer Center scientist.
"What this model allows us to do is test, in patient specimens, which markers indicate the presence of lung cancer stem cells," said Batra, senior author of the study. "Our ultimate goal is to define lung cancer and the cells that cause it so we can develop more effective therapies."
The study appears in the June issue of PLoS One.
Two competing theories of how cancer originates have been weighed by scientists for decades. In one theory, all the cells of a tumor are the same, with an equal capacity to divide and form new tumors. The other theory holds that only a few, select cells from a tumor have the ability to initiate a new tumor - the cancer stem cells. In the last decade, scientists have been able to isolate leukemia stem cells as well as brain and breast cancer stem cells. Many scientists believe that most, if not all, cancers will one day be traced back to these stem cells.
Only a small percentage of cells in a tumor are cancer stem cells, making them hard to find and even more difficult to target. Current cancer therapies are designed to target dividing cells, and the treatments do kill the majority of the cancer cells. But cancer stem cells can lay dormant and survive chemotherapy as well as the molecularly targeted treatments now being used. Because they're not actively dividing, they're invisible to conventional treatment methods.
At some point, the cancer stem cells begin their process of self-renewal and differentiation, creating a new tumor. This explains why people can remain cancer free for years and still suffer a recurrence.
Lung cancer, Batra said, is not a single disease but a collection of sub-types with different characteristics. Some lung cancers are invasive and spread quickly throughout the body, while some become drug-resistant. There may be a single lung cancer stem cell causing the different sub-types, or there may be a different lung cancer stem cell responsible for each. Since cancer stem cells are known to possess unique properties - a predisposition to metastasize and to be drug-resistant - Batra has proposed to extract candidate cancer stem cells directly from clinical specimens based on the markers they express, and then validate these cells functionally.
In an effort to find lung cancer stem cells, Batra and his team collected specimens from patients with malignant pleural effusions, a condition in which an abnormal amount of fluid collects between the thin layers of tissue lining the outside of the lung and the wall of the chest cavity.
They had found in previous attempts that culturing lung cancer cells from tumors in Petri dishes did not work well. The cells that grew were not representative of the heterogeneous cells found in a tumor. Batra and his team sought to grow cells in an environment that was as close to that in which the tumor grows as possible.
By using the fluid from the pleural effusions, Batra hoped to be able to create a microenvironment in which the tumor cells would remain heterogeneous and enable researchers to more easily identify candidate cancer stem cells.
"Using the same environment the tumors were extracted from allows us to grow a much broader variety of tumor cells," Batra said. "There's much more heterogeneity."
To provide proof of concept, Batra looked for both cell surface and epigenetic markers associated with cancer stem cells and found signatures for most of those markers in the cells they grew.
"We were able to establish cultures in vitro with high efficiency using the novel strategy that utilized an autologous tumor microenvironment," the study states. "In this primary culture model, we have been able to provide proof-of-concept that candidate lung cancer stem cells are present, that candidate lung cancer stem cells can be maintained over time in this environment, and we can live sort candidate lung cancer stem cells from these primary cultures to evaluate their phenotype in various bioassays."
Batra and his team were successful seven out of seven times in growing heterogeneous cell cultures from seven different patient specimens. Each of the seven specimens had molecular features indicative of cancer stem cells.
"We feel we were able to do this because we used not just the tumor cells but also the cells that accompany the tumor cells and the fluid they are living and growing in," Batra said. "This will allow us to develop a more representative model of lung cancer."
Judith C. Gasson, Jonsson Cancer Center director, said understanding lung cancer stem cells could lead to novel therapies that will better fight this disease, which kills more than 160,000 Americans every year.
"Jonsson Cancer Center researchers have been at the forefront of developing the current wave of targeted therapies that have been so successful in fighting cancer. But those treatments don't reach the cancer stem cells," Gasson said. "We need to understand the biology of the cancer stem cell so we can develop the next new wave of molecularly targeted therapies that go after those important cells."
The four-year study was funded by Veterans Affairs Biomedical Research Funds.
<hr>Adapted from materials provided by University of California - Los Angeles (http://www.ucla.edu/), via EurekAlert! (http://www.eurekalert.org/), a service of AAAS.
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Rich66

06-17-2009, 01:21 PM

http://www.genengnews.com/media/images/v2-5/GEN_logo.gif (http://www.genengnews.com/news/http//www.genengnews.com/) Jun 12 2009, 12:00 AM EST

Opinion: A Stem of Hope for Cancer Treatments

GEN News Highlights

President Obama’s promise of hope and change came early to stem cell research. Indeed, a friendlier federal funding environment is already enabling more researchers to explore the potential of embryonic stem cells to repair and regenerate the human body. With no evidence of how these stem cells will work in humans, though, or that they will solve more problems than they could create, the first approved stem cell therapy is still years if not decades away. While change will most certainly remain in the stem cell forecast, hope is likely to be more variable.
While headlines have been highlighting the use of stem cells as therapeutic agents, large pharma is showing a growing interest in companies studying cancer stem cells (CSCs) as therapeutic targets. CSCs can be thought of as stem cells gone haywire to produce tumors instead of tissue. Over the last five years, there has been an exponential rise in publications in the CSC arena with findings demonstrating presence of these in almost all cancer types. Given the pace of aggressive clinical developments and wide interest in the burgeoning field, there is reason to have hope in the potential of CSC therapies to change the cancer treatment paradigm.
The evil cousin of stem cells, CSCs are believed to generate tumors in the same way that their relatives generate normal tissue. Although it is not known whether CSCs arise from mutations in normal stem cells or from tumor cells that acquire stem-like properties, a growing body of evidence suggests that they are the root cause of cancer.
CSCs appear to constitute a tiny but deadly portion of the overall tumor mass. One hypothesis for the recurrence of tumors post surgery and despite radiation and chemotherapy is that CSCs can survive treatment and in some cases migrate from the initial tumor site to cause this recurrence. If this turns out to be the case, then targeting and destroying these CSCs will clearly be critical to ensuring long-term cancer-free survival.
Recent Findings
Although the first conclusive evidence of CSCs was published in Nature Medicine more than a decade ago, considerable evidence that they may be effectively targeted has mounted just in the last year. In early 2008, data presented at the “European Breast Cancer Conference” in Berlin showed that 45 women treated with GlaxoSmithKline’s (http://www.gsk.com/) (GSK) Tyverb prior to surgery had a reduction of more than 60% in the size of their secondary breast tumors along with a reduction in the number of breast cancer stem cells.
Additionally, last July scientists from the University of Michigan Comprehensive Cancer Care Center (http://www.mcancer.org/) suggested that the highly effective response of breast cancer patients treated with Genentech’s (http://www.gene.com/) Herceptin, which is a mAb, may be due to its specificity against HER2 over-expressing breast cancer cells. HER2 is also highly expressed on breast cancer stem cells. So, the antibody is not only targeting breast cancer cells but also cancer stem cells.
Similar converging evidence from other tumor models has spurred a number of companies both large and small to seek innovative biotherapeutics against CSCs. In the last 18 months GSK inked a $1.4 billion deal with OncoMed (http://www.genengnews.com/news/bnitem.aspx?name=27900549&source=genwire), and Roche acquired Arius Research for $200 million (http://www.genengnews.com/news/bnitem.aspx?name=39183529&source=genwire).
Three Attack Strategies
Investigations currently in progress target cancer stem cells using one of three approaches: small molecules, mAbs, or vaccines. Small molecule therapies work by perturbing the signaling pathway of cancer stem cells to put brakes on tumorogenesis. mAbs, on the other hand, are focused on recognizing certain markers that are highly expressed on CSCs but not on normal cells or normal stem cells. Lastly, active immunotherapy utilizes the native immune system to recognize and destroy cancer stem cells while leaving normal cells intact. While a few companies have been started de novo to focus on these programs, a number of existing compounds are also being tested for their effect on cancer stem cells.
The use of mAbs as CSC-targeting agents has only recently begun to be explored in clinical trials. Last year, OncoMed (http://www.oncomed.com/) initiated a study with its lead candidate, OMP-21M18, to treat previously treated solid tumors with potential applicability in multiple cancers. The target has not been disclosed, but the strength of the preclinical data was sufficiently strong to ink a lucrative deal with GSK. The other mAb that entered the clinic last year was ARH-460-16-2, developed by Arius Research and subsequently acquired by Roche (http://www.roche.com/), targeting a variant of CD44 present on cancer stem cells in solid tumors.
There is significant research being done to identify various CSC markers. One of these markers, CD133 (Prominin-1), has been identified as the most important, as it is overexpressed in a large variety of CSCs. In addition, a number of recent studies have demonstrated poor prognosis in brain tumor patients with high concentration of CD133 in primary tumors, suggesting lower odds of survival in cases where CSCs are present.
Seattle Genetics (http://www.seagen.com/) in collaboration with Celera (http://www.celera.com/) has developed an anti-CD133 antibody conjugated to an immunotoxin. No plans for clinical development have been announced, so it is hard to comment much on this program except to say that the basic idea is to destroy cells that are CD133-positive. However, this creates a potential safety problem, as CD133 is also expressed at reduced levels on a number of normal and stem cells.
One way to overcome this limitation is to require multiple switches before the targeted cells are destroyed. ImmunoCellular Therapeutics (http://www.imuc.com/) has devised a peptide-based vaccine that does exactly that. Cancer cells as well as CSCs express MHC class I molecules, while normal stem cells have very low to no expression of these molecules. ImmunoCellular Therapeutics’ vaccine works by eliciting a cytotoxic T-lymphocyte response specific to MHC class I molecules and targeted at CD133-positive cells. Thus, these CTLs recognize cancer cells and CSCs but not normal stem cells. This has been demonstrated in the in vitro setting so far, and the company plans to file an IND to initiate a clinical trial later this year.
Optimism for CSC-Targeted Therapy
Preclinical models of CSC-targeting vaccines so far tend to support optimism in this approach and its potential to delay or prevent cancer recurrence. Furthermore, the success of Dendreon’s (http://www.dendreon.com/) Phase III trial of its prostate cancer vaccine offers new hope for cancer immunotherapy. By using similar vaccine technology to target what may be the root cause of cancer, there is strong reason to believe that CSC-targeting therapies will continue to revolutionize the future of cancer treatment.
Our understanding of stem cells is in its infancy today, but there can be no doubt about their potential to solve some of the most complicated health problems in both regenerative medicine as well as cancer. Regenerative medicine is much more complicated due to several stages of development that the stem cells have to undergo to regenerate tissue. However, it may be easier to find therapeutic application in cancer, where the goal is to capture and destroy these tumor-initiating stem cells. Based on several encouraging clinical and preclinical studies combined with significant interest from large pharma to acquire these early-stage assets even before they enter the clinic, a bright future may be in store for cancer stem cell therapies.

--
This story was written by Manish Singh, Ph.D., president and CEO of ImmunoCellular Therapeutics.
--
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Rich66

06-17-2009, 01:45 PM

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Lett. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Le tt.%27%29;) 2009 Jun 10. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048&itool=AbstractPlus-def&uid=19523754&db=pubmed&url=http://linkinghub.elsevier.com/retrieve/pii/S0304-3835%2809%2900372-3)<script language="JavaScript1.2"></script> Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu19523754%29;)

</dt><dd class="abstract">Side population and cancer stem cells: Therapeutic implications.

Moserle L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Moserle%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Ghisi M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ghisi%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Amadori A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Amadori%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Indraccolo S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Indraccolo%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Oncology and Surgical Sciences, University of Padova, Italy.
New studies indicate that the side population (SP) and cancer stem cells (CSC) drive and maintain many types of human malignancies. SP and CSC appear to be highly resistant to chemo- and radio-therapy and this knowledge is now reshaping our therapeutic approach to cancer. Several studies have pioneered the possibility of specifically targeting CSC and SP cells by exploiting pathways involved in drug resistance, or forcing these cells to proliferate and differentiate thus converting them into a target of conventional therapies. Moreover, certain cytokines - such as IFN-alpha - appear to modulate SP and stem cell functions, and this associates with remarkable therapeutic activity in animal models. These recent findings underscore the need of a more comprehensive view of the interactions between cytokines and key regulatory pathways in SP and CSC.
PMID: 19523754 [PubMed - as supplied by publisher]

</dd></dl>

Rich66

06-17-2009, 01:47 PM

<dl class="AbstractPlusReport"><dt class="head">1: Anticancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Anticancer% 20Res.%27%29;) 2009 Jun;29(6):2147-57.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-anticanres_full.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=19528475&db=pubmed&url=http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=19528475)
</dt><dd class="abstract"> The Hedgehog Signaling Pathway Plays an Essential Role in Maintaining the CD44+CD24-/low Subpopulation and the Side Population of Breast Cancer Cells.

Tanaka H (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanaka%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Nakamura M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Nakamura%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kameda C (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kameda%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kubo M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kubo%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Sato N (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sato%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kuroki S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kuroki%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tanaka M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tanaka%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Katano M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Katano%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. mnaka@surg1.med.kyushu-u.ac.jp.
The side population (SP) and the CD44(+)/CD24(-/low) population have been reported in separate studies to include more tumorigenic cells than other populations, and to have the ability to form new tumors and undergo heterogeneous differentiation in breast cancer tissue. However, the relationship between these two populations has not yet been explored in breast cancer cells. Here it is shown that the SP and the CD44(+)/CD24(-/low) populations are overlapping. Both populations were resistant to paclitaxel. Components of the Hedgehog (Hh) signaling pathway were more highly expressed in these cell populations at both the mRNA and protein levels compared with other populations. Furthermore, inhibition of Hh signaling activity suppressed the proliferation of both populations. The significance of Hh signaling activity in the proliferation of both populations was confirmed by the effect of an si-RNA against Gli1, a trans-activator of the Hh signaling pathway, on the proliferation of both populations. These data suggest that the Hh signaling pathway is essential for the proliferation of the tumorigenic population of breast cancer cells, and that this pathway might represent a new candidate for breast cancer therapy targeting cancer stem cells.
PMID: 19528475 [PubMed - in process
</dd></dl>

Rich66

06-17-2009, 06:30 PM

<font=-1>I believe this is related to CSCs:

ue Jun 16 13:05:36 2009 Pacific Time
</font=-1> University of Virginia Health System Scientists Find Faster, Cheaper Way to Investigate How Particular Genes Suppress or Cause Cancer

CHARLOTTESVILLE, Va., June 16 (AScribe Newswire) -- Researchers at the University of Virginia Health System have found a new way to study how genes function in living organisms, and their approach could substantially cut the time and costs that drug makers spend in searching for potential targets for new cancer therapies.
"A big problem in biology is that there are many thousands of genes. Testing the function of any one of them in a living organism, such as a mouse, has traditionally been slow and very expensive," notes Ian Macara, PhD, professor of microbiology at UVA's School of Medicine and co-author of a study published in the June 15 issue of Genes & Development. "The new technology is hundreds of times cheaper and many times faster than traditional approaches. While we used it to study the function of a specific breast-developing gene, our method can be replicated in screening for genes that can suppress tumors or cause cancer."
In Genes & Development, UVA researchers describe how they isolated mammary gland stem cells from mice and then infected the cells with a virus that enabled the scientists to manipulate a particular gene and cause it to glow green. When transplanted in mice that had undergone mastectomies, the altered stem cells regenerated entire new breasts within a few months. Because the target gene glowed green, researchers could monitor its role in the development of the new breast.
The UVA study tracked Par3, a polarity protein that controls how cells acquire particular shapes, so that they have a top and a bottom. "When we shut off this gene, the stem cells had problems differentiating into the right types of cells, causing problems with mammary development. Interestingly, the glands that formed looked very much like early, pre-malignant tumor growths," explains Luke Martin McCaffrey, PhD, a post-doctoral fellow in the Center for Cell Signaling at UVA and study co-author.
Par3's function is of interest to cancer researchers and drug developers because the protein helps regulate the shape of epithelial cells, which can become malignant when deformed. Over 90 percent of solid tumors arise from epithelial cells, and early dissemination of transformed cells to distant sites is the leading cause of death from cancer.
Related link:
http://genesdev.cshlp.org/content/23/12/1450.abstract
"The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis."
Authors:
Luke Martin McCaffrey (http://genesdev.cshlp.org/search?author1=Luke+Martin+McCaffrey&sortspec=date&submit=Submit) and Ian G. Macara (http://genesdev.cshlp.org/search?author1=Ian+G.+Macara&sortspec=date&submit=Submit)
- - - -
MEDIA CONTACT: Ellen C. McKenna, 434-982-4490, ellenmckenna@virginia.edu

Rich66

06-20-2009, 08:36 PM

<dl class="AbstractPlusReport"><dt class="head">1: Expert Opin Ther Targets. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Expert%20Op in%20Ther%20Targets.%27%29;) 2009 Jul;13(7):823-37.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.expertopin.com-templates-jsp-_midtier-_ashley-images-Ashley100x25.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3204&itool=AbstractPlus-def&uid=19530986&db=pubmed&url=http://www.informapharmascience.com/doi/abs/10.1517/14728220903005616) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu19530986%29;)
</dt><dd class="abstract"> Targeting CD133 antigen in cancer.

Ferrandina G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ferrandina%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Petrillo M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Petrillo%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Bonanno G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bonanno%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Scambia G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Scambia%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Catholic University, Gynecologic Oncology Unit, L.go A. Gemelli 1, 86100 Campobasso, Italy. gabriella.ferrandina@libero.it
BACKGROUND: Much attention has been focused on CD133 as a marker of cancer cells with stem-cell-like ability. In the cancer stem cells (CSCs) model, only a small proportion of tumour cells are able to self-renew extensively, while the bulk of cells proceed to differentiate into committed heterogeneous clones. On the basis of the involvement of CSCs in tumourigenesis and treatment resistance, it is conceivable that only eradication of CSCs can lead to a cancer cure. OBJECTIVE: To highlight the most recent evidence about the role of CD133 as a marker of CSCs in human tumours, and the therapeutic perspectives associated with its specific targeting. METHODS: A literature search through Medline to locate published full articles using the following key words for selection: 'CD133 and cancer targeting', 'CD133 and chemo resistance', and 'CD133 and molecular pathways'. Only studies in English are considered. RESULTS/CONCLUSIONS: The role of CD133 as a marker of CSCs has been documented in several human neoplasms; its expression seems to predict unfavourable prognosis. Novel therapeutic strategies aimed at targeting molecular pathways critical for CD133+ CSCs survival are being examined.
PMID: 19530986 [PubMed - in process]
</dd></dl>

Rich66

06-20-2009, 08:40 PM

<dl class="AbstractPlusReport"><dt class="head">1: J Biol Chem. (javascript:AL_get(this,%20'jour',%20'J%20Biol%20C hem.');) 2009 Jun 15. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-jbc_full_free.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=19531476&db=pubmed&url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=19531476) <script language="JavaScript1.2"></script>Links (javascript:PopUpMenu2_Set(Menu19531476);)
</dt><dd class="abstract"> Cytotoxicity mediated by the FASL-activated apoptotic pathway in stem cells.

Mazar J (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mazar%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Thomas M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Thomas%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Bezrukov L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bezrukov%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Chanturia A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chanturia%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Pekkurnaz G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pekkurnaz%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Yin S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Yin%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kuznetsov SA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kuznetsov%20SA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Robey PG (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Robey%20PG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Zimmerberg J (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Zimmerberg%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
National Institutes of Health, United States.
While it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fasmediated apoptosis of activated lymphocytes, and find both Fas and FasL expression by primary BMSCs. Jurkat cells, or activated lymphocytes, were each killed by BMSCs after 72 hrs of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase 8 -/- Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues.
PMID: 19531476 [PubMed - as supplied by publisher]
</dd></dl>

Rich66

06-24-2009, 04:25 PM

<dl class="AbstractPlusReport"><dt class="head">

</dt><dt class="head">Not a hugely informative abstract, but included to add a hollywood dimension...via Hungary.

</dt><dt class="head">

</dt><dt class="head">1: Cytometry A. (javascript:AL_get(this, 'jour', 'Cytometry A.');) 2009 Jan;75(1):67-74.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www3.interscience.wiley.com-aboutus-images-wiley_interscience_150x34.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3058&itool=AbstractPlus-def&uid=19051297&db=pubmed&url=http://dx.doi.org/10.1002/cyto.a.20690) <script language="JavaScript1.2"></script>Links (javascript:PopUpMenu2_Set(Menu19051297);)
</dt><dd class="abstract"> Die hard: are cancer stem cells the Bruce Willises of tumor biology?

Fábián A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22F%C3%A1bi%C3%A1n%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Barok M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Barok%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Vereb G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Vereb%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Szöllosi J (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sz%C3%B6llosi%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Biophysics and Cell Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
In recent years, an exponentially growing number of studies have focused on identifying cancer stem cells (CSC) in human malignancies. The rare CSCs could be crucial in controlling and curing cancer: through asymmetric division CSCs supposedly drive tumor growth and evade therapy with the help of traits shared with normal stem cells such as quiescence, self-renewal ability, and multidrug resistance pump activity. Here, we give a brief overview of techniques used to confirm the stem cell-like behavior of putative CSCs and discuss markers and methods for identifying, isolating, and culturing them. We touch on the limitations of each marker and why the combined use of CSC markers, in vitro and in vivo assays may still fail to identify all relevant CSC populations. Finally, the various experimental findings supporting and contradicting the CSC hypothesis are summarized. The large number of tumor types thus far with a subpopulation of uniquely tumorigenic and therapy resistant cells suggests that despite the unanswered questions and inconsistencies, the CSC hypothesis has a legitimate role to play in tumor biology. At the same time, experimental evidence supporting the established alternative theory of clonal evolution can be found as well. Therefore, a model that describes cancer initiation and progression should combine elements of clonal evolution and CSC theory.
PMID: 19051297 [PubMed - indexed for MEDLINE
</dd></dl>

Rich66

06-24-2009, 04:31 PM

<dl class="AbstractPlusReport"><dt class="head">1: Stem Cells. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Stem%20Cell s.%27%29;) 2009 Jun 18. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www3.interscience.wiley.com-aboutus-images-wiley_interscience_150x34.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3058&itool=AbstractPlus-def&uid=19544473&db=pubmed&url=http://dx.doi.org/10.1002/stem.154)
</dt><dd class="abstract"> Snail and Slug mediate radio- and chemo-resistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells.

Kurrey NK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kurrey%20NK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Jalgaonkar SP (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jalgaonkar%20SP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Joglekar AV (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Joglekar%20AV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Ghanate AD (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ghanate%20AD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Chaskar PD (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chaskar%20PD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Doiphode RY (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Doiphode%20RY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Bapat SA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bapat%20SA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
National Centre for Cell Science, NCCS Complex, Pune University Campus, Ganeshkhind, Pune 411 007, INDIA.
The transcriptional repressors Snail and Slug contribute to cancer progression by mediating epithelial-mesenchymal transition (EMT), which results in tumor cell invasion and metastases. We extend this current understanding to demonstrate their involvement in the development of resistance to radiation and paclitaxel. The process is orchestered through the acquisition of a novel subset of gene targets that are repressed under conditions of stress, effectively inactivating p53-mediated apoptosis, while another subset of targets continues to mediate EMT. Repressive activities are complemented by a concurrent de-repression of specific genes resulting in the acquisition of stem cell--like characteristics. Such cells are bestowed with three critical capabilities viz. EMT, resistance to p53-mediated apoptosis and a self-renewal program, that together define the functionality and survival of metastatic Cancer Stem Cells (CSCs). EMT provides a mechanism of escape to a new, less adverse niche, resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor; while acquisition of 'stemness' ensures generation of the critical tumor mass required for progression of micro- to macro-metastases. Our findings, besides achieving considerable expansion of the inventory of direct genes targets, more importantly demonstrate that such elegant cooperative modulation of gene regulation mediated by Snail and Slug is critical for a cancer cell to acquire stem cell characteristics towards resisting radio- or chemotherapy mediated cellular stress, and this may be a determinative aspect of aggressive cancer metastases.
PMID: 19544473 [PubMed - as supplied by publisher
</dd></dl>

Rich66

06-28-2009, 01:37 PM

<table width="100%" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td valign="middle" align="left">http://www.sciencedaily.com/releases/2009/06/
090625141456.htm</td> <td id="printbutton" valign="middle" align="right"><input value="Print this page" onclick="window.print()" type="button"></td> </tr></tbody></table> Controversial Cancer Stem Cells Offer New Direction For Treatment

ScienceDaily (June 25, 2009) — In a review in Science, a University of Rochester Medical Center researcher sorts out the controversy and promise around a dangerous subtype of cancer cells, known as cancer stem cells, which seem capable of resisting many modern treatments.
The article proposes that this subpopulation of malignant cells may one day provide an important avenue for controlling cancer, especially if new treatments that target the cancer stem cell are developed and combined with traditional chemotherapy and/or radiation.
"The fact that these concepts are steadily making their way into the clinic is exciting, and suggests that the recent interest in cancer stem cells may yield beneficial outcomes in potentially unexpected ways," wrote co-authors Craig T. Jordan, Ph.D., professor of Medicine at URMC and director of the James P. Wilmot Cancer Center Translational Research for Hematologic Malignancies program; and Jeffrey Rosen, Ph.D., the C.C. Bell Professor of Molecular and Cellular Biology and Medicine at Baylor College of Medicine.
Cancer stem cells (CSCs) are a hot topic in the scientific community. First identified in 1994 in relation to acute myeloid leukemia, CSCs have now been identified in several solid tumors in mice as well. Scientists who study CSCs believe they have distinct properties from other cancer cells, and may be the first cells to undergo mutations.
Research from the past 10 years suggests that because CSCs may be the root of cancer, they also might provide a new opportunity for a treatment. Jordan and a group of collaborators, for example, are testing a new drug compound based on the feverfew plant that demonstrates great potential in the laboratory for causing leukemia CSCs to self destruct.
Another new approach, the authors said, is the use of chemical screens to search drug libraries for already approved agents that may target CSCs, or make resistant tumor cells more sensitive to chemotherapy and radiation.
Cancer stem cell biologists hypothesize that any treatment that targets the source of origin rather than simply killing all cells, healthy and malignant, would be an improvement over most conventional therapies.
Some scientists, however, are uncertain if CSCs have unique biological properties or any relevance to treatment, the authors noted. What is more likely to fuel cancer, other studies have found, are unfavorable factors in the neighboring cells surrounding the tumor, such as mutated genes, proteins that encourage cell growth, and a poor immune system, for instance.
The most challenging issue facing CSC biologists is that the number and type of cancer stem cells can vary from patient to patient. In some tumor samples, for example, CSCs are rare while in others they constitute a large portion of the tumor mass, the authors said.
To understand why CSCs are so variable, investigators are trying to determine what genes and pathways are responsible for activating cancers that have a poor prognosis, and whether these cancers also have a higher frequency of CSCs.
"Whether the cancer stem cell model is relevant to all cancers or not," they wrote, "it is clear that we need new approaches to target tumor cells that are resistant to current therapies and give rise to recurrence and treatment failure."
An unexpected benefit of so much attention on normal stem cells is that it has stimulated research in areas not previously the focus of cancer therapies, Jordan and Rosen said.
For example, pathways known to be important for normal stem cell self-renewal, such as the Wnt, Notch and Hedgehog(Hh) pathways, are now of increased interest due to their potential role in CSCs. The first clinical trial using an agent to block the Notch pathway in combination with chemotherapy for breast cancer has begun.
The authors conclude by spotlighting the pressing need for preclinical models to test appropriate doses and combinations of CSC therapies before they can move into human clinical trials.

Rich66

06-28-2009, 03:22 PM

Breast cancer stem cells: tools and models one can rely on

Emmanuelle Charafe-Jauffret http://www.biomedcentral.com/graphics/article/email.gif (http://www.biomedcentral.com/logon/logon.asp?msg=ce), Christophe Ginestier http://www.biomedcentral.com/graphics/article/email.gif (http://www.biomedcentral.com/logon/logon.asp?msg=ce) and Daniel Birnbaum http://www.biomedcentral.com/graphics/article/email.gif (http://www.biomedcentral.com/logon/logon.asp?msg=ce)
BMC Cancer 2009, 9:202doi:10.1186/1471-2407-9-202
<table cellpadding="0" cellspacing="0"> <tbody> <tr> <td>
</td></tr><tr> <td>Published:</td> <td>25 June 2009</td> </tr> </tbody> </table>Abstract (provisional PDF (http://www.biomedcentral.com/content/pdf/1471-2407-9-202.pdf) full text)

There is increasing evidence for the "cancer stem cell (CSC) hypothesis", which holds that cancers are driven by a cellular component that has stem cell properties, i.e. self-renewal, tumorigenicity and multi-lineage differentiation capacity. Researchers and oncologists currently realize how much it will modify the clinical approach of breast cancer since CSC apparently resist to therapy. Most clinical studies highlight the importance to better characterize the CSC population. Given the specific stem cell features, i.e. self-renewal and differentiation, which drive tumorigenesis and contribute to cellular heterogeneity, each marker and assay designed to isolate and characterize CSCs has to be functionally validated. In this review, we survey tools and markers available or promising to identify breast CSCs. We review the main models used to study breast CSC and how they challenge the CSC hypothesis.
The complete article is available as a provisional PDF (http://www.biomedcentral.com/content/pdf/1471-2407-9-202.pdf). The fully formatted PDF and HTML versions are in production.

Rich66

07-01-2009, 06:46 PM

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" valign="middle">http://www.sciencedaily.com/releases/2009/07/
090701131311.htm</td> <td id="printbutton" align="right" valign="middle"><input value="Print this page" onclick="window.print()" type="button"></td> </tr></tbody> </table> New Connection Between Cancer Cells, Stem Cells

ScienceDaily (July 1, 2009) — A molecule called telomerase, best known for enabling unlimited cell division of stem cells and cancer cells, has a surprising additional role in the expression of genes in an important stem cell regulatory pathway, say researchers at the Stanford University School of Medicine. The unexpected finding may lead to new anticancer therapies and a greater understanding of how adult and embryonic stem cells divide and specialize.
"Telomerase is the factor that accounts for the unlimited division of cancer cells," said Steven Artandi, MD, PhD, associate professor of hematology, "and we're very excited about what this connection might mean in human disease." Artandi is the senior author of the research, which will be published in the July 2 issue of the journal Nature. He is also a member of Stanford's Cancer Center.
In many ways, telomerase is the quintessential molecule of mystery — hugely important and yet difficult to pin down. Telomerase was known to stabilize telomeres, special caps that protect the ends of chromosomes. It stitches short pieces of DNA on these chromosome ends in stem cells and some immune cells, conferring a capacity for unlimited cell division denied to most of the body's other cells. Its importance is highlighted by the fact that it is inappropriately activated in more than 90 percent of cancer cells, suggesting that drugs or treatments that block telomerase activity may be effective anticancer therapies. However, its vast size, many components and relative rarity — it is not expressed in most of the body's cells — hinder attempts to learn more about it.
Artandi and his lab have spent many years identifying and studying the components of the telomerase complex. In this most recent study, they were following up on a previous finding suggesting that one part, a protein called TERT, was involved in more than just maintaining telomeres. They had discovered that overexpressing TERT in the skin of mice stimulated formerly resting adult stem cells to divide — even in the absence of other telomerase components. "This was a pretty clear hint that TERT was involved in something more than just telomere maintenance," he said.
Artandi and his colleagues recognized that the cells' response to TERT mimicked that seen when another protein, beta-catenin, was overexpressed in mouse skin. Beta-catenin is a component of a vital signaling cascade known as the Wnt pathway, which is important in development, stem cell maintenance and stem cell activation. Stanford developmental biologist and professor Roeland Nusse, PhD, a collaborator on the current study, identified the first Wnt molecule in 1982.
In this study, Artandi and his colleagues purified the TERT protein from cultured human cells and found that it was associated with a chromatin-remodeling protein implicated in the Wnt pathway. They showed that overexpression of TERT in the presence of the remodeling protein enhanced the expression of Wnt-inducible genes. Finally, they found that TERT is required for mouse embryonic stem cells to respond appropriately to Wnt signals and that blocking TERT expression impairs the development of frog embryos.
"This is completely novel," said Artandi, who went on to show that TERT physically occupies the upstream promoter regions of the genes. "No one had any idea that TERT was directly regulating the Wnt pathway." He speculates that interfering with the protein's Wnt-associated activity may be a faster way to inhibit cancer cells than blocking telomerase activity, which depends on the gradual shortening of telomeres with each cell division.
"The Wnt pathway and telomerase activity are two separate but coherent functions in stem cell self-renewal and cancer cell proliferation," said Artandi. "Nature evolved a way to connect these two crucial functions by recruiting a component of telomerase directly into the Wnt pathway." The researchers are now investigating what role TERT may play in normal and cancerous cells.
In addition to Artandi and Nusse, other Stanford collaborators on the current study include postdoctoral scholars Jae-Il Park, PhD, Jinkuk Choi, PhD, and Marina Shkreli, PhD; graduate students Andrew Venteicher, PhD, and Peggie Cheung; and research assistants Sohee Jun and Woody Chang. The research was funded by the National Cancer Institute and the California Breast Cancer Research Program.

Rich66

07-02-2009, 12:22 PM

1: Curr Mol Med. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Mol% 20Med.%27%29;) 2009 May;9(4):425-34.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.bentham-direct.org-images-ben_pubmed_flag1.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3037&itool=AbstractPlus-def&uid=19519400&db=pubmed&url=http://www.bentham-direct.org/pages/content.php?CMM/2009/00000009/00000004/0005M.SGM) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu19519400%29;)
<dd class="abstract">
Hypoxic tumor microenvironment and cancer cell differentiation.

Kim Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kim%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lin Q (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lin%20Q%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Glazer PM (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Glazer%20PM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Yun Z (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Yun%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Hypoxia or oxygen deficiency is a salient feature of solid tumors. Hypoxic tumors are often resistant to conventional cancer therapies, and tumor hypoxia correlates with advanced stages of malignancy. Hypoxic tumors appear to be poorly differentiated. Increasing evidence suggests that hypoxia has the potential to inhibit tumor cell differentiation and thus plays a direct role in the maintenance of cancer stem cells. Studies have also shown that hypoxia blocks differentiation of mesenchymal stem/progenitor cells, a potential source of tumor-associated stromal cells. It is therefore likely that hypoxia may have a profound impact on the evolution of the tumor stromal microenvironment. These observations have led to the emergence of a novel paradigm for a role of hypoxia in facilitating tumor progression. Hypoxia may help create a microenvironment enriched in poorly differentiated tumor cells and undifferentiated stromal cells. Such an undifferentiated hypoxic microenvironment may provide essential cellular interactions and environmental signals for the preferential maintenance of cancer stem cells. This hypothesis suggests that effectively targeting hypoxic cancer stem cells is a key to successful tumor control.
PMID: 19519400 [PubMed - in process]
</dd>

Rich66

07-14-2009, 10:50 AM

John Dick: careful assays for cancer stem cells

http://www.nature.com/stemcells/2009/0903/090326/full/stemcells.2009.47.html

A couple highlights:

How can understanding heterogeneity help with cancer therapies?

For years, the goal has been to achieve the highest tumour-kill frequency. The problem is some cells are more potent than other cells, and on top of that these cells have mechanisms that make them more resistant.
The whole idea of a cancer stem cell was raised to explain heterogeneity. If a tumour isn't heterogeneous in some function, the CSC model isn't wrong so much as irrelevant.
If you're saying that all cells can acquire these stem cell properties, that's really supporting the stochastic models — that's saying that depending on the external or internal environment, any cell could be a cancer stem cell. If there's randomness to it, you're left with the idea that every cell has equal potential, and that's a fundamentally different concept from the hierarchical model where it's more intrinsic to the stem cells

Rich66

07-14-2009, 11:00 AM

http://www.stemcell.com/technical/aldh.aspx

The ALDEFLUOR<sup>®</sup> and ALDECOUNT<sup>®</sup> reagent systems offer a novel approach to the identification, enumeration and isolation of stem cells and progenitor cells based on aldehyde dehydrogenase (ALDH) enzyme activity. ALDH is highly expressed by stem and progenitor cells of various lineages, including hematopoietic, endothelial, mesenchymal, neural and mammary.<sup>1-</sup>
<sup></sup>

Rich66

07-14-2009, 05:28 PM

Nature Reports Stem Cells
Published online: 12 March 2009 | <abbr title="Digital Object Identifier">doi</abbr>:10.1038/stemcells.2009.38
Treatment encourages more and more aggressive brain cancer stem cells

Simone Alves<sup>1 (http://www.nature.com/stemcells/2009/0903/090312/full/stemcells.2009.38.html#a1)</sup>
Regulation is controlled by PTEN, PI3K/Akt and drug-effluxing ABCG2
Some chemotherapeutics used to target gliomas may actually increase the cancer stem cell population and make tumours more aggressive.
Working in mice genetically engineered to have gliomas, Eric Holland and his team at the Memorial Sloan-Kettering Cancer Center in New York showed that a previously identified population of brain cells known as the side population is more tumorigenic than other cells in the brain. The proportion of cells belonging to the side population (SP) was also several-fold larger in glioma-susceptible mice compared to normal mice, and this population increased in the absence of the tumour suppressor gene PTEN. SP cells from gliomas were able to generate neurospheres in vitro, suggesting that this population can harbour brain cancer stem cells.
SP cells make high levels of the protein ATP binding cassette transporter (ABCG2), a molecular pump that actively shuttles drugs out of cells, protecting them from toxic effects. These cells also efflux fluorescent dye, allowing researchers to track the cells.
Although ABCG2 does not seem responsible for starting cancer, it does seem important for sustaining the cells in the SP, which are more likely to be cancer stem cells. Blocking ABCG2 with small molecules dramatically lowered the number of SP cells and also made them more susceptible to the cancer drug mitoxantrone.
ABCG2, in turn, is regulated by other proteins. Holland found that blocking the PI3K/Akt pathway ablates ABCG2's ability to efflux mitoxantrone. Exactly how this happens is unclear, but Holland's results indicate that it is the activity rather than the expression of the protein that is regulated.
Treatment for glioma often relies on temozolomide, a drug which, although not a substrate of ABCG2, seems to select for SP cells and drives cells to become more stem like, allowing cancer to recur. Holland believes that better characterization of the SP might facilitate combination therapies that target both these cells and the bulk of the tumour. "You can't ignore this subset of cells like the SP cells, because they do behave differently to the rest of the tumour."
"This paper really pulls together a number of observations regarding the side population, PTEN and Akt that have been made before and turns them into a cohesive story," says Jeremy Rich, chair of stem cell biology at the Cleveland Clinic in Ohio. "What is interesting for general stem cell biology is how the side population phenotype in normal stem cells is regulated by PTEN and Akt, a pathway which is vital in all cells. And what is the role of the ABCG2 transporter?"
Related articles

How breast cancer resists treatment (http://www.nature.com/uidfinder/10.1038/stemcells.2009.21)
Cancer stem cells, being common (http://www.nature.com/uidfinder/10.1038/stemcells.2008.153)
Top of page (http://www.nature.com/stemcells/2009/0903/090312/full/stemcells.2009.38.html#top)Reference

Bleau, A-M. et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumour stem-like cells. Cell Stem Cell 4, 226–235 (2009).

Rich66

07-16-2009, 01:59 PM

1: Breast Cancer Res Treat. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res%20Treat.%27%29;) 2009 Jul 12. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--production.springer.de-OnlineResources-Logos-springerlink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3055&itool=AbstractPlus-def&uid=19597705&db=pubmed&url=http://dx.doi.org/10.1007/s10549-009-0458-2) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu19597705%29;)
<dd class="abstract">
Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence.

Rhodes LV (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rhodes%20LV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Muir SE (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Muir%20SE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Elliott S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Elliott%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Guillot LM (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Guillot%20LM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Antoon JW (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Antoon%20JW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Penfornis P (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Penfornis%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tilghman SL (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tilghman%20SL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Salvo VA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Salvo%20VA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Fonseca JP (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fonseca%20JP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lacey MR (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lacey%20MR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Beckman BS (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Beckman%20BS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), McLachlan JA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22McLachlan%20JA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Rowan BG (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rowan%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Pochampally R (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pochampally%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Burow ME (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Burow%20ME%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Medicine, Section of Hematology & Medical Oncology, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
Adult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer and integrate into the tumor stroma. We demonstrate here the effect of hMSCs on primary breast tumor growth and the progression of these tumors to hormone independence. Co-injection of bone marrow-derived hMSCs enhances primary tumor growth of the estrogen receptor-positive, hormone-dependent breast carcinoma cell line MCF-7 in the presence or absence of estrogen in SCID/beige mice. We also show hormone-independent growth of MCF-7 cells when co-injected with hMSCs. These effects were found in conjunction with increased immunohistochemical staining of the progesterone receptor in the MCF-7/hMSC tumors as compared to MCF-7 control tumors. This increase in PgR expression indicates a link between MCF-7 cells and MSCs through ER-mediated signaling. Taken together, our data reveal the relationship between tumor microenvironment and tumor growth and the progression to hormone independence. This tumor stroma-cell interaction may provide a novel target for the treatment of estrogen receptor-positive, hormone-independent, and endocrine-resistant breast carcinoma.
PMID: 19597705 [PubMed - as supplied by publisher]

</dd>

Rich66

07-17-2009, 07:42 PM

<dl class="AbstractPlusReport"><dt class="head">1: Am J Clin Pathol. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Am%20J%20Cl in%20Pathol.%27%29;) 2009 Aug;132(2):237-45.

</dt><dd class="abstract">Circulating and disseminated tumor cells in the management of breast cancer.

Ross JS (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ross%20JS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Slodkowska EA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Slodkowska%20EA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Pathology and Laboratory Medicine, Mail Code 81, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA.
Despite the advances in early detection and treatment of cancer, patients continue to die of the disease even when they seek care at an early stage. For patients with breast cancer, it is now possible to detect circulating tumor cells (CTCs) in the bloodstream and disseminated tumor cells (DTCs) in the bone marrow by using immunocytochemical and molecular methods. CTCs and DTCs have been found to share similar genotypic and phenotypic characteristics with so-called breast cancer stem cells, a finding that could potentially explain the eventual relapse of disease in a patient previously considered to have been cured by primary therapy. In some studies, the presence of CTCs or DTCs at the time of diagnosis of breast cancer is an independent adverse prognostic variable. However, before CTC/DTC testing can achieve standard-of-care status, there must be improvement in the sensitivity, precision, and reproducibility of the detection methods.
</dd></dl>1: Cancer Lett. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Le tt.%27%29;) 2009 Jul 18. [Epub ahead of print]

<dd class="abstract">
Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer.

Theodoropoulos PA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Theodoropoulos%20PA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Polioudaki H (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Polioudaki%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Agelaki S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Agelaki%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kallergi G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kallergi%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Saridaki Z (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Saridaki%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mavroudis D (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mavroudis%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Georgoulias V (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Georgoulias%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece.
The CD44(+)/CD24(-/low) and ALDH1(+) cell phenotypes are associated with stemness and enhanced tumorigenic potential in breast cancer. We assessed the expression of CD44, CD24 and ALDH1 on tumor cells circulating in the peripheral blood (CTCs) of patients with metastatic breast cancer using triple-marker immunofluorescence microscopy. Among a total of 1439 CTCs identified in 20 (66.7%) out of 30 patients, 35.2% had the stem-like/tumorigenic phenotype CD44(+)/CD24(-/low), whereas 17.7% of the CTCs analyzed in seven patients, were ALDH1(high)/CD24(-/low). In conclusion, we report the existence of a subpopulation of CTCs with putative stem cell progenitor phenotypes in patients with metastatic breast cancer.
PMID: 19619935 [PubMed - as supplied by publisher]

</dd>

Rich66

07-18-2009, 10:37 AM

http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www3.interscience.wiley.com-aboutus-images-wiley_interscience_150x34.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3058&itool=AbstractPlus-def&uid=19598259&db=pubmed&url=http://dx.doi.org/10.1002/ijc.24573) <script language="JavaScript1.2"></script>Links (javascript:PopUpMenu2_Set(Menu19598259);) CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

Hong SP (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hong%20SP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Wen J (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wen%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Bang S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bang%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Park S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Park%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Song SY (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Song%20SY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine-resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC-1 cells. Gemcitabine-resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere-forming activity than parental cells. After high-dose gemcitabine treatment to eliminate most of the cells, CD44(+) cells proliferated and reconstituted the population of resistant cells.ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose-dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. CD44(+)CD24(+)ESA(+) cells remained as a small subset in the resistant cell population. Among ATP-binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44-positive tumors showed poor prognosis. These data indicate that cancer stem-like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. (c) 2009 UICC.
PMID: 19598259 [PubMed - as supplied by publisher

Rich66

07-27-2009, 09:54 PM

Controversial Cancer Stem Cells Offer New Direction For Treatment

26 Jun 2009 <input onclick="return printPage()" value="Click to Print" type="button">

In a review in Science, a University of Rochester Medical Center researcher sorts out the controversy and promise around a dangerous subtype of cancer cells, known as cancer stem cells, which seem capable of resisting many modern treatments.

The article proposes that this subpopulation of malignant cells may one day provide an important avenue for controlling cancer, especially if new treatments that target the cancer stem cell are developed and combined with traditional chemotherapy and/or radiation.

"The fact that these concepts are steadily making their way into the clinic is exciting, and suggests that the recent interest in cancer stem cells may yield beneficial outcomes in potentially unexpected ways," wrote co-authors Craig T. Jordan, Ph.D., professor of Medicine at URMC and director of the James P. Wilmot Cancer Center Translational Research for Hematologic Malignancies program; and Jeffrey Rosen, Ph.D., the C.C. Bell Professor of Molecular and Cellular Biology and Medicine at Baylor College of Medicine.

Cancer stem cells (CSCs) are a hot topic in the scientific community. First identified in 1994 in relation to acute myeloid leukemia, CSCs have now been identified in several solid tumors in mice as well. Scientists who study CSCs believe they have distinct properties from other cancer cells, and may be the first cells to undergo mutations.

Research from the past 10 years suggests that because CSCs may be the root of cancer, they also might provide a new opportunity for a treatment. Jordan and a group of collaborators, for example, are testing a new drug compound based on the feverfew plant that demonstrates great potential in the laboratory for causing leukemia CSCs to self destruct.

Another new approach, the authors said, is the use of chemical screens to search drug libraries for already approved agents that may target CSCs, or make resistant tumor cells more sensitive to chemotherapy and radiation.

Cancer stem cell biologists hypothesize that any treatment that targets the source of origin rather than simply killing all cells, healthy and malignant, would be an improvement over most conventional therapies.

Some scientists, however, are uncertain if CSCs have unique biological properties or any relevance to treatment, the authors noted. What is more likely to fuel cancer, other studies have found, are unfavorable factors in the neighboring cells surrounding the tumor, such as mutated genes, proteins that encourage cell growth, and a poor immune system, for instance.

The most challenging issue facing CSC biologists is that the number and type of cancer stem cells can vary from patient to patient. In some tumor samples, for example, CSCs are rare while in others they constitute a large portion of the tumor mass, the authors said.

To understand why CSCs are so variable, investigators are trying to determine what genes and pathways are responsible for activating cancers that have a poor prognosis, and whether these cancers also have a higher frequency of CSCs.

"Whether the cancer stem cell model is relevant to all cancers or not," they wrote, "it is clear that we need new approaches to target tumor cells that are resistant to current therapies and give rise to recurrence and treatment failure."

An unexpected benefit of so much attention on normal stem cells is that it has stimulated research in areas not previously the focus of cancer therapies, Jordan and Rosen said.

For example, pathways known to be important for normal stem cell self-renewal, such as the Wnt, Notch and Hedgehog(Hh) pathways, are now of increased interest due to their potential role in CSCs. The first clinical trial using an agent to block the Notch pathway in combination with chemotherapy for breast cancer has begun.

The authors conclude by spotlighting the pressing need for preclinical models to test appropriate doses and combinations of CSC therapies before they can move into human clinical trials.

Source:
Leslie Orr
University of Rochester Medical Center <hr size="1"> Article URL: http://www.medicalnewstoday.com/articles/155541.php

Rich66

07-28-2009, 05:25 PM

<table align="center" border="0" width="600"><tbody><tr><td>Stem-Like Cells Identified in Benign Tumors
</td></tr><tr><td><table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td>http://www.modernmedicine.com/modernmedicine/sitewide/images/clear_dot.gif</td></tr></tbody></table></td></tr><tr><td><subtitle>Cells have capability of generating new tumors in transplanted animals; show drug resistance
<table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td>http://www.modernmedicine.com/modernmedicine/sitewide/images/clear_dot.gif</td></tr></tbody></table></subtitle><table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td align="left" valign="top">
Jul 27, 2009
<source_name></source_name><source_detail>
</source_detail></td></tr></tbody></table><script language="JavaScript" src="http://www.modernmedicine.com/modernmedicine/sitewide/js/spacing.js"></script><script language="JavaScript" src="http://www.modernmedicine.com/modernmedicine/sitewide/js/articlepopwin.js"></script>MONDAY, July 27 (HealthDay News) -- Benign tumors contain stem-like cells that can be serially transplanted to generate new tumors, suggesting that such cells in benign as well as malignant tumors may be targets for anti-tumor therapies, according to a study published in the July issue of the British Journal of Cancer.
Q. Xu, Ph.D. of Cedars-Sinai Medical Center in Los Angeles, and colleagues isolated stem-like cells from hormone-producing and non-producing pituitary tumors from eight patients and transplanted them into immune-deficient mice.
The researchers found that the stem-like cells generated new tumors that were genetically identical to the original tumors, and that the stem-like cells isolated from these new tumors generated genetically identical tumors after transplantation into other mice. They also found that the stem-like cells were resistant to chemotherapy, suggesting that stem-like cells may be partly responsible for cancer relapse in some types of cancer.
"The conclusions from this study may have applications to understanding pituitary tumors, as well as implications in cancer stem cell theory in general," the authors conclude.
The study was funded in part by the National Institutes of Health and the Italian Association for Neurological Research.
Abstract (http://www.nature.com/bjc/journal/v101/n2/abs/6605142a.html)
Full Text (subscription or payment may be required) (http://www.nature.com/bjc/journal/v101/n2/full/6605142a.html)

British Journal of Cancer (2010) 102, 789–795. doi:10.1038/sj.bjc.6605551 www.bjcancer.com (http://www.bjcancer.com/)
Published online 26 January 2010
Hypoxia inducible factors in cancer stem cells

J M Heddleston<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, Z Li<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, J D Lathia<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, S Bao<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, A B Hjelmeland<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup> and J N Rich<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>
<sup>1</sup>Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland 44195, OH, USA
Correspondence: Professor JN Rich, E-mail: richj@ccf.org
Received 14 October 2009; Revised 8 December 2009; Accepted 22 December 2009; Published online 26 January 2010.

Top of page (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#top)Abstract

Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment.

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Rich66

08-27-2009, 08:37 PM

http://www.sciencedaily.com/releases/2009/08/090827141340.htm

excerpt:
This work may also shed new light on cancer. "Cancer cells, when starved, are very susceptible to cell death. However, cancer stem cells, or progenitor cells, often thrive and flourish during starvation in cell-culture experiments. When nutrition is restored, these cells can trigger rapid regrowth. Consequently, understanding how germline stem cells in C. elegans survive starvation may help appreciate how cancers survive treatments aimed at starving tumors," he said.

(maybe related to some responses to anti-angiogenisis drugs when stopped?)

Rich66

09-09-2009, 08:22 PM

<dl class="AbstractPlusReport"><dt class="head">1: Nat Med. (javascript:AL_get(this,%20'jour',%20'Nat%20Med.') ;) 2009 Sep;15(9):1010-2. Epub 2009 Sep 4.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.nature.com-images-lo_nm.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3094&itool=AbstractPlus-def&uid=19734877&nlmid=9502015&db=pubmed&url=http://dx.doi.org/10.1038/nm0909-1010)
</dt><dd class="abstract"> Cancer stem cells: mirage or reality?

Gupta PB (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gupta%20PB%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Chaffer CL (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chaffer%20CL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Weinberg RA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Weinberg%20RA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
The similarities and differences between normal tissue stem cells and cancer stem cells (CSCs) have been the source of much contention, with some recent studies calling into question the very existence of CSCs. An examination of the literature indicates, however, that the CSC model rests on firm experimental foundations and that differences in the observed frequencies of CSCs within tumors reflect the various cancer types and hosts used to assay these cells. Studies of stem cells and the differentiation program termed the epithelial-mesenchymal transition (EMT) point to the possible existence of plasticity between stem cells and their more differentiated derivatives. If present, such plasticity would have major implications for the CSC model and for future therapeutic approaches.
PMID: 19734877 [PubMed - in process
</dd></dl>

Rich66

10-21-2009, 04:40 PM

<dl class="AbstractPlusReport"><dt class="head">1: AAPS J. (javascript:AL_get(this,%20'jour',%20'AAPS%20J.'); ) 2009 Oct 20. [Epub ahead of print]
</dt><dd class="abstract"> MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications.

Desano JT (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Desano%20JT%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Xu L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Xu%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Radiation Oncology, Division of Cancer Biology, University of Michigan, 4424E Med Sci I, 1301 Catherine St., Ann Arbor, MI, 48109-5637, USA.
MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a variety of cellular, physiological, and developmental processes. Aberrant expressions of miRNAs are connected to human diseases such as cancer. Cancer stem cells are a small subpopulation of cells identified in a variety of tumors that are capable of self-renewal and differentiation. Dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer. Furthermore, cancer stem cells are a very likely cause of resistance to current cancer treatments, as well as relapse in cancer patients. Understanding the biology and pathways involved with cancer stem cells offers great promise for developing better cancer therapies, and might one day even provide a cure for cancer. Emerging evidence demonstrates that miRNAs are involved in cancer stem cell dysregulation. Recent studies also suggest that miRNAs play a critical role in carcinogenesis and oncogenesis by regulating cell proliferation and apoptosis as oncogenes or tumor suppressors, respectively. Therefore, molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation.
PMID: 19842044 [PubMed - as supplied by publisher
</dd></dl>

Rich66

10-28-2009, 03:55 PM

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Stem Cell Therapies Aimed at Patient Trials Get $230 Million
Share (javascript:togShareLinks('shr_v');) | Email (?Subject=Bloomberg%20news:%20%20Stem%20Cell%20The rapies%20Aimed%20at%20Patient%20Trials%20Get%20$23 0%20Million%20&body=%20Stem%20Cell%20Therapies%20Aimed%20at%20Pat ient%20Trials%20Get%20$230%20Million%20%0D%0A%0D%0 A%20http%3A//www.bloomberg.com/apps/news%3Fpid%3Demail_en%26sid%3DaQLXM6AJyJ9k) | Print (http://www.bloomberg.com/apps/news?pid=20670001&sid=aQLXM6AJyJ9k#) | A (http://www.bloomberg.com/apps/news?pid=20670001&sid=aQLXM6AJyJ9k#) A (http://www.bloomberg.com/apps/news?pid=20670001&sid=aQLXM6AJyJ9k#) A (http://www.bloomberg.com/apps/news?pid=20670001&sid=aQLXM6AJyJ9k#)

By Rob Waters
Oct. 28 (Bloomberg) -- California’s stem-cell agency handed out $229.7 million to 14 research teams, an infusion intended to enable tests of treatments in humans to start within four years.
The agency acted today to stimulate commercial drug development, making eight grants to researchers collaborating with companies, said Alan Trounson (http://search.bloomberg.com/search?q=Alan+Trounson&site=wnews&client=wnews&proxystylesheet=wnews&output=xml_no_dtd&ie=UTF-8&oe=UTF-8&filter=p&getfields=wnnis&sort=date:D:S:d1), the agency’s president. The top-ranked project is a partnership of the City of Hope (http://www.cityofhope.org/about/Pages/default.aspx), a nonprofit treatment center near Los Angeles, and Sangamo Biosciences (http://www.bloomberg.com/apps/quote?ticker=SGMO%3AUS), a Richmond, California-based biotechnology company. They received $14.6 million to work on a new method for using stem cells to treat AIDS and the virus that causes it, HIV.
To be eligible for funding, applicants must show they would be ready in four years to gain U.S. Food and Drug Administration clearance to start human studies. Involving companies with experience running clinical trials and dealing with regulators will speed the process, Trounson said.
“We feel more confident if there’s a company associated with the projects,” Trounson said yesterday in a telephone interview. “We’re going to be very closely involved with the groups. They have to achieve milestones and if they don’t, we’ll terminate the grant and reinvest our money elsewhere.”
Funding agencies from Canada and the United Kingdom added about $43 million to the amount coming from the 4-year-old state agency, called the California Institute for Regenerative Medicine (http://www.cirm.ca.gov/).
$20 Million Loan
One of the awards, for $20 million, goes to closely held Novocell, based in San Diego, to accelerate its effort to develop a stem-cell therapy for diabetes. The money is a long- term loan to the company. Other grant projects will develop treatments for diabetes, sickle cell anemia, leukemia, heart disease and other conditions.
Stanford University and the University of California, Los Angeles, were the top recipients, with each getting funding for three projects. Stanford’s grants totaled $51.7 million and UCLA will get $49.2 million.
A UCLA-led effort to target so-called cancer stem cells to treat brain, colon and other solid tumors will get an additional $20 million from the Cancer Stem Cell Consortium, a project partly funded by the Canadian government. That project is led by Dennis Slamon (http://search.bloomberg.com/search?q=Dennis+Slamon&site=wnews&client=wnews&proxystylesheet=wnews&output=xml_no_dtd&ie=UTF-8&oe=UTF-8&filter=p&getfields=wnnis&sort=date:D:S:d1), who helped develop the cancer drug Herceptin marketed by Roche Holding AG.
The projects were chosen by a committee of board members and outside experts from among applications submitted by California institutions.
Several of the projects pursue research in new directions. Two of the grants -- to the City of Hope-Sangamo Biosciences partnership and to the UCLA AIDS Institute -- will support efforts to develop new approaches to the treatment of AIDS. Both attempt to boost immunity to the disease by mimicking a successful stem-cell treatment of a patient last year in Germany.
To contact the reporter on this story: Rob Waters (http://search.bloomberg.com/search?q=Rob+Waters&site=wnews&client=wnews&proxystylesheet=wnews&output=xml_no_dtd&ie=UTF-8&oe=UTF-8&filter=p&getfields=wnnis&sort=date:D:S:d1) in San Francisco at rwaters5@bloomberg.net.
Last Updated: October 28, 2009 14:49 EDT

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Rich66

10-30-2009, 11:48 PM

Nippon Rinsho. (javascript:AL_get(this,%20'jour',%20'Nippon%20Rin sho.');) 2009 Oct;67(10):1863-7.
[Cancer stem cell concepts--lesson from leukemia]

[Article in Japanese]
Nitta E (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nitta%20E%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Suda T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Suda%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Cell Differentiation, Keio University School of Medicine.
Although monoclonal in origin, most tumors appear to contain heterogeneous populations of cancer cells. One possible explanation of this tumor heterogeneity is that human tumors are not merely monoclonal expansions of a single transformed cell, but rather caricatures of normal tissues, and their growth is sustained by cancer stem cells (CSCs). This hierarchy model, first developed for human myeloid leukemias, is supported by mounting evidences today. This conceptual shift has important implications, not only for understanding tumor biology but also for developing and evaluating effective anticancer therapies. We review a history of the development of cancer stem cell concepts in hematology and recent topics of leukemic stem cells (LSCs).

PMID: 19860180 [PubMed - in process]

Rich66

11-01-2009, 03:09 PM

Survival of the Fittest: Cancer Stem Cells in Therapeutic
Resistance and Angiogenesis
Christine E. Eyler1 and Jeremy N. Rich1,2,3,4
1Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham NC
27710, USA.
2Department of Medicine, Duke University Medical Center, Durham NC 27710, USA.
3Department of Surgery, Duke University Medical Center, Durham NC 27710, USA.
4Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham NC 27710,
USA.
Abstract
In an increasing number of cancers, tumor populations called cancer stem cells (CSCs) or tumor initiating cells have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemo- and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-Catenin and Notch signalling. Novel targeted therapies against the DNA damage checkpoint or stem cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are anti-angiogenic and vascular targeting agents which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of anti-angiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

Introduction

Increasing evidence supports tumors as complex heterogeneous organ-like systems with a hierarchical cellular organization, rather than simply as collections of homogeneous tumor cells. Normal stem cells can replicate to populate an organ during normal organogenesis and tumors initiate when cells develop an unrestricted capacity for sustained proliferation. In both scenarios the initiating cell, whether a normal stem cell or a tumorigenic cell, retains the capacity to generate diverse progeny at various levels of differentiation, from uncommitted pluripotent stem cells to committed progenitor cells to fully differentiated senescent descendent cells. In this way, the tumor cell population itself is heterogeneous, adding to the heterogeneity provided by the immune, stromal and vascular cells that are also present in tumors. Some of the cells within the “aberrant” cancer organ<sup>1 (http://www.ncbi.nlm.nih.gov/pubmed/11689955)</sup>, the tumor, have the potential for continued proliferation, despite the frequent differentiated phenotype displayed by the majority of the tumor cells. The phylogeny of these tumor cells thus suggests the existence of a cell population that retains the ability to self-renew while also often possessing the capacity to generate progeny that differentiate. In other words, this leads us to hypothesize the existence of cancer stem cells (CSCs), alternately called tumor initiating cells and stem-like cancer cells, within tumors that are responsible for tumorigenesis as well as maintenance of the tumor bulk.
Many advanced cancers recur despite the use of chemotherapeutic and radiation modalities that initially lead to therapeutic responses. For example, irradiation of glioblastomas (GBMs) can lead to significant radiographic responses, yet these tumors invariably recur and lead to patient death. Frequently, glioblastomas recur in a nodular pattern suggesting a clonal or polyclonal source of recurrent tumor cells that are able to withstand conventional cytotoxic therapies, including radiation therapy, to cause recurrence of disease. Furthermore, recurrent tumors also demonstrate heterogeneity within the tumor cell population with regards to the presence of both CSCs and non-CSCs as well as in histological and cytogenetic differences<sup>2 (http://www.ncbi.nlm.nih.gov/pubmed/9816106)</sup>, suggesting that the CSCs that populated the original tumor may have withstood the treatments to repopulate the recurrent tumor even after the bulk of the tumor has been removed by resection or chemoradiation therapy<sup>3 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R3)</sup>.
The idea of CSCs as being the source of post-therapeutic tumor recurrence is not a new one<sup>4 (http://www.ncbi.nlm.nih.gov/pubmed/16488983)</sup>. Indeed, scientists in the late nineteenth century proposed that a rare population of cells with stem-like properties may be the source of tumors<sup>5 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R5)</sup><sup>-</sup><sup>7 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R7)</sup>. As technologies improved, people began noticing that cancers contained cells that differed in their abilities to proliferate in colony formation assays<sup>8 (http://www.ncbi.nlm.nih.gov/pubmed/5115909)</sup> and spleen repopulation assays<sup>9 (http://www.ncbi.nlm.nih.gov/pubmed/14047954)</sup><sup>-</sup><sup>11 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R11)</sup>, suggesting that there may be sub-populations of cells with varied self-renewal capacity. The advances in technology through the 1980s and 1990s allowed for more efficient separation of cells based on cell marker phenotypes, leading to the prospective identification of normal hematopoietic stem cells in 1988<sup>12 (http://www.ncbi.nlm.nih.gov/pubmed/2898810)</sup>. More recently, Bonnet and Dick<sup>13 (http://www.ncbi.nlm.nih.gov/pubmed/9212098)</sup> validated the theoretical existence of tumorigenic stem cells in cancers with the identification of a population of primitive leukemic cells resembling hematopoietic stem cells that could give rise to acute myelogenous leukemia with multi-lineage differentiation in immunodeficient mice. Subsequently, improvements in the ability to prospectively isolate stem-like cells have generated evidence that a variety of solid tumors contain similar stem-like tumor cells. Though sometimes only present in very small numbers in human tumors, CSCs have the ability to generate tumors that recapitulate the original tumor when xenotransplanted into in animals, whereas the remaining non-CSC tumor bulk most often cannot<sup>4 (http://www.ncbi.nlm.nih.gov/pubmed/16488983)</sup><sup>,</sup><sup>14 (http://www.ncbi.nlm.nih.gov/pubmed/16990388)</sup><sup>,</sup><sup>15 (http://www.ncbi.nlm.nih.gov/pubmed/16990346)</sup>. The most substantiated CSC selection methods have been developed for leukemias<sup>13 (http://www.ncbi.nlm.nih.gov/pubmed/9212098)</sup>, central nervous system tumors including glioma<sup>16 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R16)</sup><sup>-</sup><sup>20 (http://www.ncbi.nlm.nih.gov/pubmed/12203386)</sup>, and breast cancer<sup>21 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R21)</sup>, but similar selection techniques appear to be applicable to other tumors, with accumulating evidence for existence of a CSC subpopulation in tumors of the colon<sup>22 (http://www.ncbi.nlm.nih.gov/pubmed/17122772)</sup><sup>,</sup><sup>23 (http://www.ncbi.nlm.nih.gov/pubmed/17122771)</sup>, pancreas<sup>24 (http://www.ncbi.nlm.nih.gov/pubmed/17283135)</sup>, prostate<sup>25 (http://www.ncbi.nlm.nih.gov/pubmed/16449977)</sup>, melanoma<sup>26 (http://www.ncbi.nlm.nih.gov/pubmed/16230395)</sup>, liver<sup>27 (http://www.ncbi.nlm.nih.gov/pubmed/17570225)</sup> and head and neck<sup>28 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R28)</sup>.
It is of no small concern that in a variety of tumors, CSCs seem to be particularly resistant to conventional chemo- and radiation therapies compared with the more differentiated cells in the non-CSC compartment. Furthermore, the CSCs seem to be particularly adept in stimulating angiogenesis to promote tumor growth and increase overall tumor aggressiveness both before and after therapy. In fact, there is an increasing body of evidence suggesting that radioresistance, chemotherapy resistance, and angiogenesis in these CSCs in humans could partially explain tumor recurrence in advanced or aggressive tumors treated with radiation.

Evidence for Radiation Resistance in Cancer Stem Cells

Radiation therapy remains the most effective non-surgical intervention for glioblastomas, though these tumors invariably recur after radiation therapy to result in patient death. Therefore, determination of the mechanisms of radioresistance in these tumors and others could lead to advances in the treatment of cancer. In our studies of radioresistance in glioblastomas<sup>29 (http://www.ncbi.nlm.nih.gov/pubmed/17051156)</sup>, we utilized short term cell cultures derived from primary human tumor specimens and xenografted tumors to investigate radiation responses in cell populations enriched for CSCs versus non-CSCs. This system allows us to bypass the many disadvantages involved in use of high-passage established cell lines, as serum-containing media induces differentiation. We showed that the population of cells enriched for glioma CSCs was dramatically increased by irradiation and that irradiated CSCs have survival advantages relative to the non-CSC population. CSCs are then able to give rise to tumors that have both CSCs and more differentiated non-CSCs. Radioresistant tumors displayed an increased percentage of CD133+ cells than the parent cell population. Furthermore, radiation had little effect on the ability of CSCs to regrow tumors.
We speculated that the CSC-enriched cell population might avoid radiation-induced cell death through activation of DNA damage repair mechanisms. Indeed, the non-CSCs had higher levels of apoptosis following irradiation relative to the CSC population. Radiation caused equal levels of damage to all cancer cells but CSCs repaired the damage more rapidly than non-stem cancer cells. Cancer cells, like all cells, respond to DNA damage through the activation of complex detection and repair mechanisms. The DNA damage and replication checkpoint includes ataxia telangiectasia mutated (ATM) and the checkpoint kinases, Chk1 and Chk2, that become activated upon genotoxic stress to initiate cell cycle arrest and attempted repair or apoptosis if the damage is too great. CSCs activate the DNA damage checkpoint more readily than matched non-stem cells. In fact, the CSCs display a basal activation of the checkpoint, indicating that they are primed to respond to genomic insults. Inhibition of the Chk1/2 kinases with a small molecule inhibitor disrupted the radioresistance of CSC-enriched cells in an in vitro colony formation assay and in in vivo tumor growth, suggesting that an intact Chk1/2 response is critical to the radioresistance of glioblastoma CSCs. Hence, this Chk1/2 response could develop into a worthwhile target in efforts to develop agents able to sensitize CSCs to radiation therapy (Figure 1a, b (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F1/)). Notably, the checkpoint proteins Chk1 and Chk2 and the rest of the DNA damage response cascade may contribute to tumor initiation, as activation of the DNA damage checkpoint occurs early in tumorigenesis<sup>30 (http://www.ncbi.nlm.nih.gov/pubmed/15829965)</sup><sup>,</sup><sup>31 (http://www.ncbi.nlm.nih.gov/pubmed/15829956)</sup>. However, it is probable that these CSCs employ more than one mechanism of cell survival after radiation, due to the multiple cellular changes caused by radiation, such as DNA damage and reactive oxygen species formation. Several studies using breast cancer cell lines have made efforts to examine other potential radioresistance mechanisms in CSC populations.
<table class="thumb-caption" style="clear: both; width: 100%;" border="0" cellpadding="0" cellspacing="0"><tbody><tr align="left" valign="top"><td class="thumb-cell">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0001.gifhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0001.gif

(http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F1/)</td><td class="caption-cell">Figure 1 (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F1/)CSC-sensitizing agents in radiation therapy and chemotherapy. Tumors contain both CSCs (pink) and non-stem cancer cells (yellow). CSCs may preferentially survive monotherapy with ionizing radiation (A) or cytotoxic chemotherapies (C), leading to tumor (more ...) (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F1/)

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The Wnt/β-catenin pathway has recently been implicated in the radiation resistance in mammary progenitor cells as well as cells expressing CSC markers in breast cancer cell lines. Woodward et al. showed in a murine mammary epithelial cell (MEC) culture that radiation treatment results in enrichment for the stem- and progenitor cell-containing side population, and particularly augments the stem cell antigen (Sca) positive compartment of the side population cells<sup>32 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R32)</sup>. Wnt-induced mammary hyperplasias (from MMTV-driven Wnt-1 transgenic mice) show an increased side population relative to matched controls, and MECs from mice with a conditionally stabilized β-catenin allele showed a higher proportion of side population cells after radiation than matched controls. Interestingly, Sca<sup>+</sup> side population cells, but not Sca- cells, had high levels of activated β-catenin by flow cytometry after irradiation. The same group also determined a role for the Wnt/β-catenin pathway in radioresistance of CSCs in an immortalized mammary gland cell line<sup>33 (http://www.ncbi.nlm.nih.gov/pubmed/17227796)</sup>. In this system, overexpression of β-catenin in the Sca<sup>+</sup> cells enhanced self-renewal in a mammosphere formation assay and expression of a dominant negative β-engrailed decreased self-renewal. Intriguingly, these alterations affected the total levels of survivin, an anti-apoptotic protein that is upregulated in these cells after irradiation. No knockdown analysis of survivin was completed, so it is difficult to say that it is definitely the mediator of radioresistance in these Sca<sup>+</sup> cells, but it is interesting as a subject for further study. These studies on Wnt/β-catenin signalling provide an insight as to another possible mechanism for CSC radioresistance, but await confirmatory animal and clinical studies.
Because radioresistance in CSCs may occur via concurrent but distinct mechanisms, these data regarding Wnt/β-catenin involvement in cell survival and self-renewal after irradiation correlate with the concept that CSCs have amplified DNA damage repair mechanisms through Chk1/2 activation, as shown by Bao et al<sup>29 (http://www.ncbi.nlm.nih.gov/pubmed/17051156)</sup>. Normal stem cells activate the Wnt/β-catenin signalling axis during development<sup>34 (http://www.ncbi.nlm.nih.gov/pubmed/15829953)</sup>, and several lines of research in non-CSC systems suggest that activation of the Wnt/β-catenin pathway promotes DNA damage tolerance. For example, Ku70 and PARP-1 compete with β-catenin for binding to the transcription T-cell factor 4 (Tcf-4), which is the downstream mediator for many of the effects caused by activation of the Wnt/β-catenin pathway<sup>35 (http://www.ncbi.nlm.nih.gov/pubmed/17283121)</sup>. When DNA is damaged, PARP-1 is modified to prevent its interaction with Tcf-4, thus allowing Ku70 to bind in a complex with β-catenin to activate the Wnt pathway cellular effects. Therefore, DNA damage may enhance β-catenin activity. In light of this, while possibly promoting the ability of CSCs to survive extensive DNA damage until lethal damage can be repaired, the Wnt/β-catenin pathway promotes genomic instability in colon cancer<sup>36 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R36)</sup> and may promote conversion of non-tumorigenic stem cells to glioma CSCs through the destabilization of the genome<sup>37 (http://www.ncbi.nlm.nih.gov/pubmed/17332509)</sup>. This signalling axis could play its role by allowing radiated cells to tolerate DNA damage, while the Chk1/2 kinases cause cell cycle arrest until lethal DNA damage can be repaired. Alternatively, these pathways could both promote genomic instability while allowing tumor cells to survive after irradiation, thus accelerating the rate of genetic change in the tumor.
Other pathways have also been implicated as playing roles in CSC radioresistance. Phillips et al.<sup>38 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R38)</sup> showed that CSC-enriched mammosphere cultures of established breast cancer cell lines showed decreased sensitivity to radiation in clonogenic assays relative to adherent cells from the same line, while the numbers of the CSCs in the culture increased in response to fractionated radiation. The levels of reactive oxygen species were reduced in the mammosphere cultures, indicating higher levels of radical scavengers in these CSC-enriched cultures. Interrogation of a possible role of the Notch signalling axis on this radioresistance revealed a modest induction of Jagged-1 expression on the surface of non-adherent CSC-enriched cells after fractionated radiation as well as increases in the levels of activated Notch-1 in the culture media of CSC-enriched cells, indicating that altered activity in the Notch pathway may partially explain the apparent radioresistance present in the CSC fraction. Though this study showed a correlation between the levels of Jagged and activated Notch-1 and radiation treatment, more in depth interrogation might reveal whether this pathway is either necessary or sufficient for CSC radioresistance. The Hedgehog-Gli1 pathway has been implicated in human glioma CSC self-renewal and tumorigenicity, so it is conceivable that this pathway could be involved in CSC-mediated tumor recurrence after radiation therapy<sup>39 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R39)</sup>. In unfractionated glioma cultures, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as the multitargeted kinase inhibitor ZD6474 and AG1478 have been shown to block radiation and chemoradiation resistance, respectively, in the tumor bulk<sup>40 (http://www.ncbi.nlm.nih.gov/pubmed/16061883)</sup><sup>,</sup><sup>41 (http://www.ncbi.nlm.nih.gov/pubmed/12154034)</sup> and a dominant negative form of EGFR can enhance radiosensitivity in glioma cell lines<sup>42 (http://www.ncbi.nlm.nih.gov/pubmed/15475464)</sup>. CSCs require EGF for maintenance in culture, so it is entirely possible that a pathway downstream of EGFR may contribute to CSC radioresistance. In fact, loss of the tumor suppressor PTEN, which has reduced activity in many tumors due to silencing or mutation and which functions to oppose EGFR-mediated signalling through the Akt kinase, has been shown in mouse embryonic stem cells to prevent cell cycle arrest in response to radiation by restricting Chk1 to the cytoplasm, ultimately leading to genetic instability<sup>43 (http://www.ncbi.nlm.nih.gov/pubmed/16023594)</sup>.

CSCs and Chemotherapy Resistance

Most cytotoxic therapies used for cancer therapy damage DNA or disrupt mitosis to induce cell death in highly proliferative tumor cells. The apparent resistance of CSCs to radiation-induced DNA damage toxicity suggests that perhaps CSCs may also play a role in mediating chemotherapy resistance in tumors. Indeed there have been several studies implicating CSCs as being chemoresistant in a variety of different cancers. Recently, it was reported that a subpopulation of pancreatic cancer cells functionally resemble stem cells and also have a strong resistance to gemcitabine both in vitro and in vivo<sup>44 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R44)</sup>. Recent data suggests that preferential Akt activity may confer chemotherapy resistance to hepatocellular carcinoma CSCs<sup>45 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R45)</sup>. One group found that CSCs from gliomas display marked resistance to several chemotherapeutic agents (temozolamide, carboplatin, VP16 and Taxol) relative to the non-CSC population<sup>46 (http://www.ncbi.nlm.nih.gov/pubmed/16457726)</sup>. Colon cancer stem cells, which were shown to have baseline resistance to cell death induced by 5-fluorouracil or oxaliplatin treatment, can be chemosensitized by an interleukin-4 blocking antibody, suggesting that autocrine stimulation of IL-4 receptors on CSCs may contribute to their chemoresistant phenotype<sup>47 (http://www.ncbi.nlm.nih.gov/pubmed/18371377)</sup> and could be manipulated in efforts to sensitize CSCs to cytotoxic chemotherapies (Figure 1c, d (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F1/)).
Both normal stem cells and CSCs commonly express drug pumps such as ATP-binding cassette (ABC) transporters, including multidrug resistance transporter 1 (MDR1) and breast cancer resistance protein (BCRP). Leukemic side population cells, which are enriched for CSCs, have an amplified ability to pump chemotherapeutic drugs like daunorubicin and mitoxantrone out of the cell, suggesting that increased drug removal ability may contribute to the chemoresistance of cancer stem cells<sup>48 (http://www.ncbi.nlm.nih.gov/pubmed/11493466)</sup>, and stem-like neuroblastoma cells displayed a similar ability to pump mitoxantrone, resulting in increased cell survival<sup>49 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R49)</sup>. Specifically, the ABC transporters BCRP and MDR1 have been implicated in specifically expelling chemotherapeutic agents from cells and thus may mediate chemoresistance when expressed by CSCs. MDR1 has been shown to remove vinblastine<sup>50 (http://www.ncbi.nlm.nih.gov/pubmed/16204959)</sup> and paclitaxel<sup>51 (http://www.ncbi.nlm.nih.gov/pubmed/16467099)</sup>, while BCRP prevents accumulation of imatinib mesylate<sup>52 (http://www.ncbi.nlm.nih.gov/pubmed/15251980)</sup>, topotecan<sup>53 (http://www.ncbi.nlm.nih.gov/pubmed/15908806)</sup> and methotrexate<sup>54 (http://www.ncbi.nlm.nih.gov/pubmed/12874005)</sup>.
In addition to possessing an increased capacity for drug efflux, CSCs also express molecular metabolic mediators like aldehyde dehydrogenase 1 (ALDH1) that have been shown to confer resistance to cyclophosphamide in normal stem cells<sup>55 (http://www.ncbi.nlm.nih.gov/pubmed/8562935)</sup>. ALDH1 activity is amplified in leukemic CSCs and thus may have implications for the resistance of these cells to chemotherapeutic agents such as cyclophosphamide<sup>56 (http://www.ncbi.nlm.nih.gov/pubmed/15917471)</sup>. ALDH1 is expressed by breast CSCs and is associated with a poor prognosis<sup>57 (http://www.ncbi.nlm.nih.gov/pubmed/18371393)</sup> suggesting that chemotherapy resistance mechanisms expressed by CSCs may directly impact patient outcome. Furthermore, cellular sensitivity to chemotherapeutic agents relies upon cell cycle kinetics that will permit lethal cellular damage in highly proliferative cells. Normal stem cells cycle less frequently than the more differentiated transit-amplifying cells (thus, the designation of normal stem cells as label retaining). CSCs from acute and chronic myelogenous leukemias are relatively quiescent<sup>58 (http://www.ncbi.nlm.nih.gov/pubmed/10477735)</sup><sup>,</sup><sup>59 (http://www.ncbi.nlm.nih.gov/pubmed/11187903)</sup>, contributing to therapeutic resistance. Similar results have not been confirmed in CSCs derived from solid tumors. The rapid proliferation of solid tumor CSCs described in ex vivo assays is likely not representative of the in vivo proliferative index as CSCs are cultured with high levels of growth factors in most assays, but, it is probable that the least differentiated tumor populations mimic normal stem cells with a relatively slow rate of renewal contributing to the ability of these cells to resist chemotherapeutic agents that depend on specific cycles or on rate of cycle completion. Ultimately, the chemoresistance displayed by the CSCs in a variety of tumors as a result of increased drug efflux, metabolic alterations and cell cycle kinetics highlights the need for development of CSC radiation and chemotherapy sensitization techniques and compounds that will allow these resistant populations to be eradicated to prevent recurrence of disease.

CSCs and Angiogenesis

Clinical use of anti-angiogenic agents for neoplastic diseases has accelerated in recent years, with over 40 currently in clinical trials for various types of cancers<sup>60 (http://www.ncbi.nlm.nih.gov/pubmed/17396134)</sup>. Anti-angiogenic agents such as bevacizumab (Avastin) have shown promise as part of a combination therapy regimen in several advanced cancers, including colon cancer<sup>61 (http://www.ncbi.nlm.nih.gov/pubmed/15175435)</sup> and glioblastoma<sup>62 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R62)</sup>. Moreover, several agents that were originally developed as blocking EGFR (erlotinib, cetuximab, vandetanib) have recently been shown to have an inhibitory effect on angiogenesis by blocking the vascular endothelial growth factor (VEGF) receptor or by inhibiting pro-angiogenic protein secretion<sup>60 (http://www.ncbi.nlm.nih.gov/pubmed/17396134)</sup>. Thus, it seems as if the clinical success of several widely used and studied compounds may relate to inhibition of vascular growth in tumors. There are several theories regarding the clinical mechanism of anti-angiogenic drug benefit. One possibility is that anti-angiogenics simply destroy the vascular structure of the tumor, promoting profound tumor hypoxia and nutrient deprivation. Alternatively, it has been proposed that anti-angiogenics may transiently “normalize” the tumor vasculature, making it more efficient in delivering oxygen and drugs<sup>63 (http://www.ncbi.nlm.nih.gov/pubmed/15637262)</sup>. In addition, it appears as if some cancers may express VEGF receptors as well, raising the possibility that anti-VEGF therapies like bevacizumab actually have direct anti-tumor effects. Understanding the mechanism of anti-angiogenic agents will permit their optimal clinical use.
Interestingly, CSCs contribute to tumor angiogenesis. We have found that CSCs produce much higher levels of VEGF in both normoxic and hypoxic conditions than the non-CSC population, and this CSC-mediated VEGF production leads to amplified endothelial cell migration and tube formation in vitro<sup>64 (http://www.ncbi.nlm.nih.gov/pubmed/16912155)</sup>. When we supplemented these endothelial migration and tube-formation assays with the VEGF-blocking antibody bevacizumab, the in vitro endothelial cell behaviors were blocked. Moreover, in vivo administration of bevacizumab potently inhibited the growth, vascularity, and hemorrhage of xenografts derived from CSCs while no effects were seen on xenografts from non-CSCs. A VEGF-overexpression glioma model has recently provided supportive evidence for this as well by showing that glioblastoma CSCs overexpressing VEGF produce larger, more vascular and highly hemorrhagic tumors<sup>65 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R65)</sup>.
It appears that while angiogenesis in tumors derives significantly from CSC-secreted VEGF, CSCs themselves depend on the presence of vascular niches. Calabrese et al.<sup>66 (http://www.ncbi.nlm.nih.gov/pubmed/17222791)</sup> confirmed that CSCs generate VEGF and other factors to induce angiogenesis, but also showed that CSCs themselves are dependent on factors created by the vasculature itself (Figure 2ahttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0002.gif (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F2/)). In this way, CSCs mimic normal stem cells, which also seem to be dependent on vascular niches and factors secreted by the vasculature<sup>67 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R67)</sup><sup>,</sup><sup>68 (http://www.ncbi.nlm.nih.gov/pubmed/12951572)</sup>. Factors like leukaemia inhibitory factor (LIF), brain derived neurotrophic factor (BDNF) and pigment epithelial derived factor (PEDF) have been implicated in normal stem cell maintenance<sup>67 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R67)</sup>, so these factors may also regulate endothelium-derived CSC niche maintenance. Thus, CSCs and angiogenesis can positively feed-back on each other to promote tumor development and maintenance and represents an area of tumor biology that could be clinically manipulated to provide anti-tumor effects (Figure 2bhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0002.gif (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F2/)).
<table class="thumb-caption" style="clear: both; width: 100%;" border="0" cellpadding="0" cellspacing="0"><tbody><tr align="left" valign="top"><td class="thumb-cell">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0002.gifhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/bin/nihms-123201-f0002.gif

(http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F2/)</td><td class="caption-cell">Figure 2 (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F2/)Anti-angiogenic agents may target both tumor vasculature formation and CSC niche maintenance. (A) CSCs generate pro-angiogenic factors to stimulate angiogenesis while the tumor vasculature aids in maintaining CSC self-renewal and maintenance. (B) Anti-angiogenic (more ...) (http://www.ncbi.nlm.nih.gov/pmc/articles/mid/NIHMS123201/figure/F2/)

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The interplay between CSCs, angiogenesis and the tumor vasculature may well impact the efficacy of radiation. HIF-1 a transcription factor stabilized by hypoxic conditions, increases the production of VEGF in gliomas as well as a variety of other tumor types and has been suggested as a factor that regulates a variety of tumor radioresponses. It sensitizes tumor cells to radiation through induction of ATP metabolism, proliferation and p53 activation but it also allows endothelial cell survival<sup>69 (http://www.ncbi.nlm.nih.gov/pubmed/16098463)</sup>. These complex effects on radiation sensitivity have not yet been dissected, but we have noted that irradiated CSC-derived tumors are particularly vascular and hemorrhagic<sup>29 (http://www.ncbi.nlm.nih.gov/pubmed/17051156)</sup>, indicating that hypoxia-mediated endothelial cell survival after radiation may contribute to the angiogenesis and tumor growth noted in post-radiation tumors. Furthermore, CSCs may be enriched by hypoxic conditions<sup>70 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739000/#R70)</sup>, thus stabilizing HIF in these cells. These observations suggest that HIF-mediated radioresistance in tumors may be intimately related to the often hypoxic CSCs, and that targeting the CSCs or their vascular niche may have a CSC radiosensitizing effect in addition to simply preventing the development of vascular structures that supply the tumor bulk. In fact, recent clinical studies have showed enhanced anti-tumor cell effects when anti-angiogenic therapy is combined with radiation<sup>71 (http://www.ncbi.nlm.nih.gov/pubmed/11034104)</sup><sup>-</sup><sup>73 (http://www.ncbi.nlm.nih.gov/pubmed/16029810)</sup>. Given the evidence for CSC dependence on tumor vasculature, combining radiation therapy with anti-angiogenic therapies has promise in possibly mediating targeted anti-CSC effects to promote prolonged recurrence-free survival.

Clinical Applications of CSC Therapeutic Resistance and Angiogenesis

Despite the recent advances in basic science research in the CSC field on the subject of chemotherapy and radiotherapy resistance, the fact remains that clinicians continue to face the challenge of recurrent or metastatic cancer despite maximal therapy. As molecular mediators of therapeutic resistance in CSCs are established, developing clinically useful inhibitors to target these pathways should be prioritized. It seems reasonable that combining radiation therapy with an agent that radiosensitizes CSCs, an agent that targets tumor angiogenesis and an agent that can debulk the mass of the tumor, would be a good approach to rationally advancing the treatment of solid tumors. For example, use of a radiosensitizing Chk1/2 inhibitor with the anti-angiogenic therapy bevacizumab and the cytotoxic drug temozolamide could amplify responses in tumors that will be irradiated. Local delivery of therapeutics to post-resection residual tumor cells through implantation of drug-eluting wafers similar to the Gliadel wafers used in glioblastoma resection cavities could be helpful in targeting the radiosensitization and cytotoxic agents to tumors for which drug delivery is a barrier, such as brain tumors. The potential for targeting CSC populations to prevent recurrence after anti-tumor therapy as part of a personalized medicine approach is also very promising, as elimination of the tumor bulk is critical during treatment and this aspect of therapy could be guided very powerfully by the molecular profile of the overall tumor.
Finally, a word should be said about developing anti-CSC therapies that have minimal or no effect on normal stem cells. Though stem cells in non-hematopoietic tissues still have poorly defined roles, they could potentially be critical for mediating tissue responses to injury. Development of targeted anti-CSC therapies should take this into account and should aim to affect molecules and pathways that are not crucial for normal stem cell maintenance. The existence of such a therapeutic window has been suggested by one recent study of normal hematopoietic stem cells and leukemic CSCs with deletions in the tumor suppressor Pten<sup>74 (http://www.ncbi.nlm.nih.gov/pubmed/16598206)</sup>. The authors demonstrate that while the CSCs and the resultant leukemias are effectively treated by rapamycin treatment, the proliferation of non-cancerous Pten<sup>−/−</sup> hematopoietic stem cells is maintained. This indicates the differential sensitivity of normal and cancer stem cells and suggests strongly that therapies targeting the CSCs without affecting normal stem cells is possible. Though still in its infancy, it seems likely that the field of CSC therapeutic resistance could lead to the development of unique targeted agents that may be able to sensitize these cells to chemotherapy and radiation therapy in order to improve cancer care.

Proc Natl Acad Sci U S A. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Proc%20Natl %20Acad%20Sci%20U%20S%20A.%27%29;) 2009 Dec 15;106(50):21306-11. Epub 2009 Dec 2.
Human cancers converge at the HIF-2{alpha} oncogenic axis.

Franovic A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Franovic%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Holterman CE (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Holterman%20CE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Payette J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Payette%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lee S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lee%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.

PMID: 19955413 [PubMed - in process]

Rich66

11-04-2009, 11:20 AM

Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits?
(10 pg. PDF attached below)
Ciara S. O’Brien & Sacha J. Howell & Gillian Farnie &
Robert B. Clarke
Received: 16 December 2008 / Accepted: 10 February 2009 / Published online: 28 February 2009
# Springer Science + Business Media, LLC 2009

"The concept that epithelial and other solid tumors are aberrantly developed tissues containing a developmental hierarchy including cancer stem-like cells (CSCs) and more differentiated progenitor cells is supported by accumulating evidence."

"There is no doubt that the evidence that CSCs are responsible for tumorigenesis and cancer recurrence is becoming increasingly solid and needs to be considered for therapeutic decision-making in the clinic."

"A common theme of many investigations into CSCs is that they have inherent resistance to chemo and radiotherapy. This is proposed to be due to mechanisms such as more efficient DNA damage checkpoints and survival pathways compared to more differentiated tumor
cell populations."

"Enhanced interaction between estrogen receptor signalling and growth factor tyrosine kinase pathways such as EGFR, HER2/erbB2 and IGFR mediates resistance to endocrine therapy"

"HDAC inhibitors are being used in a number of on going clinical trials including a phase II trial evaluating vorinostat in ER positive patients with metastatic breast cancer who failed prior aromatase inhibitor therapy and up to three chemotherapy regimes [95]. A report of preliminary findings presented at ASCO 2008 showed that out of the 17 enrolled patients 21% had a partial response and 29% had stable disease after treatment with vorinostat 400 mg daily for 3 of 4 weeks and tamoxifen 20 mg daily,
continuously. These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity."

Abstract
From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis.
In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the
hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells.
Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs.
As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

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Concluding Remarks
In this review, we have summarised current evidence that supporting improving our understanding of CSCs in order to explain endocrine resistance in breast cancer. The biology of breast CSCs is becoming better characterized and the data suggest that they may be resistant to several
forms of cancer therapy through diverse mechanisms. In terms of responsiveness to endocrine therapy, we can learn about CSC biology and hierarchies in breast cancer by examining what is known about the developmental hierarchy of the normal breast epithelium (Fig. 1). In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ER−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ER+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in resistant breast cancers reflects an increased proportion of stem-like
cells selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER− which would support this view. CSCs also express mesenchymal proteins which are suppressed by ER expression, further indicating the mutual exclusion between ER+ cells and the CSCs. It is likely that this is regulated at the epigenetic level, and differences in DNA methylation and chromatin organization can be observed between breast CSCs and more differentiated populations. This may in turn be regulated extrinsically by the influence of stromal elements including the stem cell
niche microenvironment associated with the vasculature, the lymph nodes and the bone marrow to which breast cancer cells often metastasise. It is known that the epigenetic programming can be remodeled by using drugs, particularly those that change the methylation and chromatin patterns of
the DNA. Such drugs can effectively differentiate the cells, including potentially the CSCs, leading to a reduction in growth factor receptors and an increase in ER+ cells, which may overcome resistance to endocrine agents in combination therapy. Such combinations are currently in clinical
trials and their outcome is eagerly anticipated. As we learn more about CSCs, differentiation and the expression and functional activity of the ER in these cells in diverse tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine
resistance in the clinic.

Rich66

11-08-2009, 01:29 PM

To evade chemotherapy, some cancer cells mimic stem cells

ATLANTA - Anti-cancer treatments often effectively shrink the size of tumors, but some might have an opposite effect, actually expanding the small population of cancer stem cells believed to drive the disease, according to findings presented today in Atlanta, Georgia at the American Association for Cancer Research's second International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

"Our experiments suggest that some treatments could be producing more cancer stem cells that then are capable of metastasizing, because these cells are trying to find a way to survive the therapy," said one of the study's investigators, Vasyl Vasko, M.D. Ph.D., a pathologist at the Uniformed Services University of the Health Sciences in Bethesda, Md.

"This may help explain why the expression of stem cell markers has been associated with resistance to chemotherapy and radiation treatments and poor outcome for patients with cancers including prostate, breast and lung cancers," Dr. Vasko said. "That tells us that understanding how to target these markers and these cells could prove useful in treating these cancers."

The cancer stem cell markers include Nanog and BMI1, both of which contribute to stem cells' defining ability to renew themselves and differentiate into different cell types, Dr. Vasko said. These same molecules are found in embryonic stem cells.

Researchers have recently debated the notion that some therapies are not capable of eradicating cancer because they do not target the cancer stem cells responsible for tumor development. To test this hypothesis, Dr. Vasko, along with scientists from the CRTRC Institute for Drug Development in San Antonio and from the Johns Hopkins University, set out to measure both stem cells markers and tumor volume before and after treatment in a mouse model.

They selected a rare form of cancer, mesenchymal chondrosarcoma (MCS), which has not been well described and for which there is no effective treatment. The researchers first determined that Nanog and BMI1 stem cell markers were more highly expressed in metastatic tumors compared to primary tumors. "This suggests that expression of the marker plays some role in development of metastasis," Dr. Vasko said.

They then applied various therapies - from VEGF inhibitors such as Avastin to the proteasome inhibitor Velcade - in mice implanted with human MSC, and analyzed the effects on tumors. Some of the treatments seemed to work, because they led to a dramatic decrease in the size of the tumors, Dr. Vasko said. But analysis of stem cell expression before and after treatment revealed that even as some anti-cancer treatments shrank tumors, they increased expression of Nanog and BMI1. "These treatments were not enough to completely inhibit tumor growth, and the cancer stem cell markers were still present," Dr. Vasko said.

Use of the agents Velcade and Docetaxel led to the most significant increase in stem cell markers within the treated tumor, while ifosfamide and Avastin inhibited expression of the markers in this cancer subtype.

"We hypothesize that the tumor escapes from chemotherapy by induction of stem cell marker expression," he said. "The small number of cells that survive the treatment could then generate another tumor that metastasizes."

Dr. Vasko doesn't know how this happens, but theorizes that "dying cells could secrete a lot of factors that induce expression of stem cell markers in other cancer cells. I think they are trying to survive and they use a mechanism from their experience of embryonic life."

American Association for Cancer Research. September 2007.

Rich66

11-08-2009, 11:34 PM

Cancer Immunol Immunother. (javascript:AL_get(this,%20'jour',%20'Cancer%20Imm unol%20Immunother.');) 2009 Aug;58(8):1185-94. Epub 2008 Dec 2.
Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells.

Mine T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mine%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Matsueda S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Matsueda%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Li Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Li%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tokumitsu H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tokumitsu%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Gao H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gao%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Danes C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Danes%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Wong KK (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wong%20KK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Wang X (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wang%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Ferrone S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ferrone%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Ioannides CG (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ioannides%20CG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. mine@med.kurume-u.ac.jp
Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen(+) (ESA) CD44(hi) CD24(lo), CD44(hi) CD133(+), and CD133(+) CD24(lo)] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEM(Res) MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEM(Sens) MCF7. The levels of Numb, and Numb-L-[P]-Ser(265) were similar in GEM(Res) and GEM(Sens) MCF7 cells. Only the levels of Numb-L (long)-Ser(295) decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEM(Res) MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112-2120) and Numb-1 (87-95) eliminated NICD(positive), CD24(hi) CD24(lo) MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.

Rich66

11-09-2009, 12:19 AM

Oncogene (2008) 27, 6120–6130; doi:10.1038/onc.2008.207; published online 30 June 2008

Full text: http://www.nature.com/onc/journal/v27/n47/full/onc2008207a.html

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

H Korkaya<sup>1 (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#aff1)</sup>, A Paulson<sup>1 (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#aff1)</sup>, F Iovino<sup>1 (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#aff1),2 (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#note1)</sup> and M S Wicha<sup>1 (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#aff1)</sup>
<sup>1</sup>Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
Correspondence: Dr H Korkaya, Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, 7110 CCGC, Ann Arbor, MI 48109, USA. E-mail: hkorkaya@med.umich.edu
<sup id="note1">2</sup>Current address: Department of Surgical and Oncological Science, University of Palermo, Italy.
Received 1 April 2008; Revised 3 June 2008; Accepted 4 June 2008; Published online 30 June 2008.

Top of page (http://www.nature.com/onc/journal/v27/n47/abs/onc2008207a.html#top)Abstract

The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20–30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demonstrated by in vitro mammosphere assays and the expression of stem cell marker aldehyde dehydrogenase (ALDH) as well as by generation of hyperplastic lesions in humanized fat pads of NOD (nucleotide-binding oligomerization domain)/SCID (severe combined immunodeficient) mice. Overexpression of HER2 in a series of breast carcinoma cell lines increases the ALDH-expressing 'cancer stem cell' population which displays increased expression of stem cell regulatory genes, increased invasion in vitro and increased tumorigenesis in NOD/SCID mice. The effects of HER2 overexpression on breast cancer stem cells are blocked by trastuzumab in sensitive, but not resistant, cell lines, an effect mediated by the PI3-kinase/Akt pathway. These studies provide support for the cancer stem cell hypothesis by suggesting that the effects of HER2 amplification on carcinogenesis, tumorigenesis and invasion may be due to its effects on normal and malignant mammary stem/progenitor cells. Furthermore, the clinical efficacy of trastuzumab may relate to its ability to target the cancer stem cell population in HER2-amplified tumors.

Rich66

11-10-2009, 03:55 PM

Biol Cell. (javascript:AL_get(this,%20'jour',%20'Biol%20Cell. ');) 2009 Nov 9. [Epub ahead of print]
Modulation of tumorigenesis and estrogen receptor-alpha expression by cell culture condition in a stem cell-derived breast epithelial cell line.

Wang KH (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wang%20KH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Kao AP (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kao%20AP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Chang CC (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chang%20CC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lee JN (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lee%20JN%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Chai CY (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chai%20CY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hou MF (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hou%20MF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Liu CM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Liu%20CM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tsai EM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tsai%20EM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Background information. The common phenotypes of cancer and stem cells suggest that cancers arise from stem cells. Estrogen is one of few most important determinants in breast cancer as shown by several convincing evidence. We have previously reported a human breast epithelial cell type (Type 1 HBEC) with stem cell characteristics and estrogen receptor alpha (ERalpha) expression. A tumorigenic cell line, M13SV1R2, was developed from this cell type following SV40 large T-antigen transfection and X-ray irradiation. The cell line, however, was not responsive to estrogen for cell growth or tumor development. In this study, we tested the hypothesis that deprivation of growth factors and hormones may change tumorigenicity and estrogen response of this cell line. Results. The M13SV1R2 cells lost its tumorigenicity after culturing in a growth factor/hormone-deprived medium for <10 passages (referred to as R2d cells) concomitant with the expression of two tumor suppressor genes, maspin and alpha-6 integrin. However, these cells acquired estrogen responsiveness in cell growth and tumor development. By immunocytochemistry, western blotting and flow cytometry analysis, , i.estrogen treatment of R2d cells was found to induce many important effects related to breast carcinogenesise. 1) the emergence of a subpopulation of cells expressing CD44+/high/CD24-/low breast tumor stem cell markers; 2) the induction of EMT; 3) the acquisition of metastatic ability; and 4) the expression of COX-2 through CD44-mediated mechanism. Conclusion. Estrogen responsive cell line with ERalpha and CD44+/CD24-/low expression can be derived from breast epithelial stem cells. The tumorigenicity and estrogen response of these cells could depend on cell culture condition. The findings of this study have implications in regard to the origins of 1) ERalpha-positive breast cancers, 2) CD44+/CD24-/low breast tumor stem cells and 3) metastatic ability of breast cancer.

PMID: 19895368 [PubMed - as supplied by publisher]

Rich66

11-15-2009, 04:30 PM

Cancer stem cells targeted to prevent relapse

By: Vivek Sinanan

Posted: 10/22/09

According to a recent paper by Richard Jones of the Hopkins Sidney Kimmel Comprehensive Cancer Center, cancer stem cells (CSCs) can help in the long-term treatment of cancer by preventing relapse.

For at least the past three decades, the existence of CSCs has been known. They are characterized as cells that are biologically similar to normal cells but have the ability to regenerate or self-renew.

According to Jones, these CSCs are only a small fraction of the total cancerous cells but, in theory, they contain all the capacity for the tumor's self-renewal.

CSCs therefore pose a major threat to contemporary cancer treatments. Because of their unique ability, they are more resistant to most standard anti-cancer therapies and treatments than other cancer cells.

Jones' research found that the CSCs tend to copy the defensive mechanisms of other stem cells. Quiescence, in which a cell goes into a dormant state, allows cancer cells to avoid detection by many anti-cancer drugs - efflux pumps, located on cell membranes, can rid the cell of toxins, while detoxifying enzymes break down foreign substances before they can do much harm. All of these mechanisms work together to keep CSCs unharmed by cancer treatments, increasing the likelihood of cancer recurrence.

New research has exposed the potential of CFCs to treat cancer. Scientists from the National Cancer Institute theorized that CSCs and their ability to resist treatment are responsible for relapses in cancer patients, and direct targeting of these stem cells could lead to eventual cures for cancer. Preliminary research has shown that they may be the key to unlocking new cancer treatments if they are directly targeted.

There are several pathways that contribute to the growth and development of normal stem cells during pre- and post-natal development in children. Research has shown that inhibiting these pathways could be effective in the treatment of not one but several types of cancers due to the stem cells' important role in cell maintenance and growth.

A second method of treatment deals with telomeres, the structures that recently won Carol Greider of Hopkins, Elizabeth Blackburn and Jack Szostak the Nobel Prize in Medicine. The survival and aging of a cell is directly linked to the length of its telomeres and the presence of telomerase, the enzyme that synthesizes telomeres.

In an experiment performed at the Dana-Faber Cancer Institute in Boston, researchers mated mice who were predisposed to cancer with mice whose telomerase had been silenced, known as "telomerase knock-out mice." The researchers found that this crossing significantly lowered the development of cancers in these mice.

This is because normal stem cells, and by extension CSCs, require telomerase to lengthen their telomeres. If cells did not have this DNA-lengthening machinery, the DNA would get shorter and shorter with each replication cycle. Genes would eventually be lost from the ends and the cell could potentially die. In normal cells, telomerase prevents rapid DNA loss from occurring, but as a person ages, telomeres, themselves, eventually shorten. In cancer cells, telomerase is over-active, re-growing DNA at lightning speed so that the cancer can continue to replicate uncontrollably. When the telomerase knock-out mice mated with their cancerous counterparts, they produced offspring who were at high risk for cancer but who could not develop their tumors because of the lack of telomerase.

There is one great limit to these new treatments. CSCs make up only a small portion of the cancerous cells in tumors, on average less than one percent. Any impact of treatments on CSCs may be masked by the large bulk of non-CSC cancer cells, and the detection methods available today are incapable of catching them all.

Nevertheless, a CSC-centered approach to
cancer treatments could one day eliminate the possibility of cancer recurrence. <hr size="1"> © Copyright 2009 News-Letter

ABCS 2009 Interview with Robert A. Weinberg, Ph.D.

http://s7.addthis.com/static/btn/v2/lg-share-en.gif (http://www.addthis.com/bookmark.php?v=250&pub=aacrnews) <script type="text/javascript" src="http://s7.addthis.com/js/250/addthis_widget.js?pub=aacrnews"> </script>
The CTRC-AACR San Antonio Breast Cancer Symposium, Dec. 9-13, 2009, attracts world leaders in cancer research and treatment, including clinical oncologists, industry leaders, basic scientists and translational researchers who are working to improve patient care with the ultimate goal of eradicating breast cancer.
Watch Robert A. Weinberg, Ph.D., a founding member of Whitehead Institute for Biomedical Research and professor of Biology at MIT, talk about "Breast Cancer Stem Cells and the Epithelial-Mesenchymal Transition."

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<embed type="application/x-shockwave-flash" allowfullscreen="true" allowscriptaccess="always" src="http://www.youtube.com/v/Tmbjj6Nzo4U&hl=en_US&fs=1&rel=0" height="295" width="480"> </object>

http://www.youtube.com/watch?v=Tmbjj6Nzo4U

bejuce

11-15-2009, 06:00 PM

"...could one day eliminate cancer recurrence." I like that! And hope this day is closer than we think!

Rich66

01-22-2010, 04:28 PM

Cancer Stem Cell (CSC) research has accelerated in the last two years

E-mail (http://www.mmdnewswire.com/component/option,com_mailto/link,aHR0cDovL3d3dy5tbWRuZXdzd2lyZS5jb20vcHJlc3Mtc mVsZWFzZS02NzQwLmh0bWw=/tmpl,component/) | Print | (http://www.mmdnewswire.com/press-release-6740/print.html) PDF (http://www.mmdnewswire.com/pdf-6740/press-release.pdf)

Cancer Stem Cell (CSC) research has accelerated in the last two years and considerable efforts are now being made to identify drug molecules that selectively target and destroy these cells. (MMD Newswire) January 20, 2010 - The Infoshop by Global Information would like to present a new market research report, " Targeting Cancer Stem Cells: Therapeutic Strategies and Pipeline Developments (2010)" by Biopharm Reports.
This 2010 report gives a comprehensive and up-to-date review of global R&D on CSCs, and strategies to target them. This includes around 40 companies or commercially based research organisations (including 27 SMEs and 8 international pharmaceutical companies) that are progressing drug discovery activities, including drug pipeline (pre-clinical to Phase III), discovery strategy, candidate molecules, drug targets, clinical trials and related areas.
Background: Many cancers contain a subset of stem-like cells believed to play a critical role in the development and progression of the disease. These cells, named Cancer Stem Cells (CSCs), have been found in leukemia, myeloma, breast, prostate, pancreatic, colon, brain, lung and other cancers. Findings suggest that CSCs are able to "seed" new tumour formation and drive metastasis. CSCs also show resistance to a number of chemotherapy drug classes and radiotherapy - which may explain why it is difficult to completely eradicate cancer cells from the body, and why recurrence remains an ever-present threat. If these findings are confirmed in the clinic, the targeting of CSCs alongside the bulk of other cancer cells will offer a new paradigm in cancer therapeutics.
To purchase this report and/or read a full description:
http://www.the-infoshop.com/report/bph107851-cancer-stem-cell.html

Clinical Study

British Journal of Cancer (2010) 102, 815–826. doi:10.1038/sj.bjc.6605553 www.bjcancer.com (http://www.bjcancer.com/)
Published online 9 February 2010
Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling

T Nakanishi<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1),5 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#note1)</sup>, S Chumsri<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1)</sup>, N Khakpour<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1)</sup>, A H Brodie<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1)</sup>, B Leyland-Jones<sup>2 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff2)</sup>, A W Hamburger<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1)</sup>, D D Ross<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff1),3 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff3)</sup> and A M Burger<sup>4 (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#aff4)</sup>

<sup>1</sup>Departments of Medicine, Pathology, Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Cancer Center (UMGCC), Baltimore, MD, USA
<sup>2</sup>Department of Hematology and Medical Oncology, Winship Cancer Center, Emory University, Atlanta, GA, USA
<sup>3</sup>Baltimore VA Medical Center, Baltimore, MD, USA
<sup>4</sup>Barbara Ann Karmanos Cancer Institute and Department of Pharmacology, Wayne State University, Detroit, MI, USA

Correspondence: Dr AM Burger, Department of Pharmacology, Wayne State University, Hudson-Webber Cancer Research Center, Barbara Ann Karmanos Cancer Institute, Rm 640.2, 4100 John R. Street, Detroit, MI 48201, USA; E-mail: amburger@wayne.edu
<sup id="note1">5</sup>Current address: Kanazawa University School of Pharmaceutical Sciences, Kanazawa, Japan.
Received 18 August 2009; Revised 21 December 2009; Accepted 22 December 2009; Published online 9 February 2010.

Top of page (http://www.nature.com/bjc/journal/v102/n5/abs/6605553a.html#top)Abstract

Background:

The expression of side-population (SP) cells and their relation to tumour-initiating cells (T-ICs) have been insufficiently studied in breast cancer (BC). We therefore evaluated primary cell cultures derived from patients and a panel of human BC cell lines with luminal- or basal-molecular signatures for the presence of SP and BC stem cell markers.

Methods:

The SPs from luminal-type BC were analysed for BC T-IC characteristics, including human epidermal growth factor receptor 2 (HER2), ERα, IGFBP7 expression and their ability to initiate tumours in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice. Pharmacological modulators were used to assess the effects of HER2 signalling and breast cancer-resistance protein (BCRP) expression on SPs.

Results:

The SP was more prevalent in the luminal subtype of BC compared with the basal subtype. HER2 expression was significantly correlated with the occurrence of an SP (r<sup>2</sup>=0.75, P=0.0003). Disappearance of SP in the presence of Ko143, a specific inhibitor of the ATP-binding cassette transporter BCRP, suggests that BCRP is the predominant transporter expressed in this population. The SP also decreased in the presence of HER2 signalling inhibitors AG825 or trastuzumab, strengthening the notion that HER2 contributed to the SP phenotype, likely through downstream AKT signalling. The SP cells from luminal-type MCF-7 cells with enforced expression of HER2, and primary cells with luminal-like properties from a BC patient, displayed enrichment in cells capable of repopulating tumours in NOD/SCID mice. Engraftment of SP cells was inhibited by pretreatment with AG825 or by in vivo treatment with trastuzumab.

Interpretation:

Our findings indicate an important role of HER2 in regulating SP and hence T-ICs in BC, which may account for the poor responsiveness of HER2-positive BCs to chemotherapy, as well as their aggressiveness.

Keywords:

SP, BC, luminal, HER2, T-ICs