HonCode

Go Back   HER2 Support Group Forums > Articles of Interest
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 06-15-2009, 08:19 AM   #21
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Mammary stem cell number as a determinate of breast cancer risk



http://breast-cancer-research.com/content/9/4/109
Rich66 is offline   Reply With Quote
Old 06-16-2009, 10:04 PM   #22
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Web address:
http://www.sciencedaily.com/releases/2009/06/
090616103323.htm
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.

Adapted from materials provided by University of California - Los Angeles, via EurekAlert!, a service of AAAS.
Email or share this story:
| More



APA

MLA
University of California - Los Angeles (2009, June 15). Cancer Researchers Develop Model That May Help Identify Cancer Stem Cells. ScienceDaily. Retrieved June 16, 2009, from http://www.sciencedaily.com* /releases/2009/06/090616103323.htm
Rich66 is offline   Reply With Quote
Old 06-17-2009, 01:21 PM   #23
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Opinion: A Stem of Hope for Cancer Treatments

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 (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 suggested that the highly effective response of breast cancer patients treated with Genentech’s 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, and Roche acquired Arius Research for $200 million.
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 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, 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 in collaboration with Celera 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 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 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.

--
Related News
Scientists Uncover Gene-Expression Signature for Prostate Cancer Stem Cells (May 20, 2008)
NextGen Acquires Pending Patent from Oxon Life Science Linked to Breast Cancer Stem Cells (Apr. 8, 2008)
Raven and Emory University Scientist Team Up for Prostate Cancer Stem Cell Research (Mar. 3, 2008)
Researchers Discover How Cancer Stem Cells Are Trapped at an Early Developmental Stage (Jan. 7, 2008)
Scientists Identify miRNA that Regulates Cancer Stem Cells (Dec. 14, 2007)


HOME | SUBSCRIBE
© 2008 Genetic Engineering & Biotechnology News, All Rights Reserved - terms of use | legal information | privacy statement | contact | about GEN | SITE MAP
Rich66 is offline   Reply With Quote
Old 06-17-2009, 01:45 PM   #24
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Cancer Lett. 2009 Jun 10. [Epub ahead of print] Links

Side population and cancer stem cells: Therapeutic implications.

Moserle L, Ghisi M, Amadori A, Indraccolo S.
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]

Rich66 is offline   Reply With Quote
Old 06-17-2009, 01:47 PM   #25
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Anticancer Res. 2009 Jun;29(6):2147-57.
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, Nakamura M, Kameda C, Kubo M, Sato N, Kuroki S, Tanaka M, Katano M.
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
Rich66 is offline   Reply With Quote
Old 06-17-2009, 06:30 PM   #26
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
I believe this is related to CSCs:


ue Jun 16 13:05:36 2009 Pacific Time
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?aut...&submit=Submit) and Ian G. Macara (http://genesdev.cshlp.org/search?aut...&submit=Submit)
- - - -
MEDIA CONTACT: Ellen C. McKenna, 434-982-4490, ellenmckenna@virginia.edu
Rich66 is offline   Reply With Quote
Old 06-20-2009, 08:36 PM   #27
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Expert Opin Ther Targets. 2009 Jul;13(7):823-37. Links
Targeting CD133 antigen in cancer.

Ferrandina G, Petrillo M, Bonanno G, Scambia G.
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]
Rich66 is offline   Reply With Quote
Old 06-20-2009, 08:40 PM   #28
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: J Biol Chem. 2009 Jun 15. [Epub ahead of print] Links
Cytotoxicity mediated by the FASL-activated apoptotic pathway in stem cells.

Mazar J, Thomas M, Bezrukov L, Chanturia A, Pekkurnaz G, Yin S, Kuznetsov SA, Robey PG, Zimmerberg J.
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]
Rich66 is offline   Reply With Quote
Old 06-24-2009, 04:25 PM   #29
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431


Not a hugely informative abstract, but included to add a hollywood dimension...via Hungary.



1: Cytometry A. 2009 Jan;75(1):67-74. Links
Die hard: are cancer stem cells the Bruce Willises of tumor biology?

Fábián A, Barok M, Vereb G, Szöllosi J.
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
Rich66 is offline   Reply With Quote
Old 06-24-2009, 04:31 PM   #30
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Stem Cells. 2009 Jun 18. [Epub ahead of print]
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, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA.
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
Rich66 is offline   Reply With Quote
Old 06-28-2009, 01:37 PM   #31
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
http://www.sciencedaily.com/releases/2009/06/
090625141456.htm
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 is offline   Reply With Quote
Old 06-28-2009, 03:22 PM   #32
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Breast cancer stem cells: tools and models one can rely on

Emmanuelle Charafe-Jauffret , Christophe Ginestier and Daniel Birnbaum
BMC Cancer 2009, 9:202doi:10.1186/1471-2407-9-202

Published: 25 June 2009
Abstract (provisional 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. The fully formatted PDF and HTML versions are in production.
Rich66 is offline   Reply With Quote
Old 07-01-2009, 06:46 PM   #33
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
http://www.sciencedaily.com/releases/2009/07/
090701131311.htm
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 is offline   Reply With Quote
Old 07-02-2009, 12:22 PM   #34
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Curr Mol Med. 2009 May;9(4):425-34. Links

Hypoxic tumor microenvironment and cancer cell differentiation.

Kim Y, Lin Q, Glazer PM, Yun Z.
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]
Rich66 is offline   Reply With Quote
Old 07-14-2009, 10:50 AM   #35
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
John Dick: careful assays for cancer stem cells


http://www.nature.com/stemcells/2009...s.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 is offline   Reply With Quote
Old 07-14-2009, 11:00 AM   #36
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
http://www.stemcell.com/technical/aldh.aspx

The ALDEFLUOR® and ALDECOUNT® 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.1-
Rich66 is offline   Reply With Quote
Old 07-14-2009, 05:28 PM   #37
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Nature Reports Stem Cells
Published online: 12 March 2009 | doi:10.1038/stemcells.2009.38
Treatment encourages more and more aggressive brain cancer stem cells

Simone Alves1
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
Cancer stem cells, being common
Top of pageReference

  1. 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 is offline   Reply With Quote
Old 07-16-2009, 01:59 PM   #38
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Breast Cancer Res Treat. 2009 Jul 12. [Epub ahead of print] Links

Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence.

Rhodes LV, Muir SE, Elliott S, Guillot LM, Antoon JW, Penfornis P, Tilghman SL, Salvo VA, Fonseca JP, Lacey MR, Beckman BS, McLachlan JA, Rowan BG, Pochampally R, Burow ME.
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]

Rich66 is offline   Reply With Quote
Old 07-17-2009, 07:42 PM   #39
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
1: Am J Clin Pathol. 2009 Aug;132(2):237-45.

Circulating and disseminated tumor cells in the management of breast cancer.

Ross JS, Slodkowska EA.
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.
1: Cancer Lett. 2009 Jul 18. [Epub ahead of print]


Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer.

Theodoropoulos PA, Polioudaki H, Agelaki S, Kallergi G, Saridaki Z, Mavroudis D, Georgoulias V.
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]

Rich66 is offline   Reply With Quote
Old 07-18-2009, 10:37 AM   #40
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Links CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

Hong SP, Wen J, Bang S, Park S, Song SY.
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 is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 09:22 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter