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 07-27-2009, 09:54 PM   #41
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Controversial Cancer Stem Cells Offer New Direction For Treatment

26 Jun 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.

Source:
Leslie Orr
University of Rochester Medical Center
Article URL: http://www.medicalnewstoday.com/articles/155541.php
Rich66 is offline   Reply With Quote
Old 07-28-2009, 05:25 PM   #42
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

Stem-Like Cells Identified in Benign Tumors
Cells have capability of generating new tumors in transplanted animals; show drug resistance

Jul 27, 2009

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
Full Text (subscription or payment may be required)






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

J M Heddleston1, Z Li1, J D Lathia1, S Bao1, A B Hjelmeland1 and J N Rich1
1Department 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 pageAbstract

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.


Rich66 is offline   Reply With Quote
Old 08-27-2009, 08:37 PM   #43
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

http://www.sciencedaily.com/releases...0827141340.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 is offline   Reply With Quote
Old 09-09-2009, 08:22 PM   #44
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

1: Nat Med. 2009 Sep;15(9):1010-2. Epub 2009 Sep 4.
Cancer stem cells: mirage or reality?

Gupta PB, Chaffer CL, Weinberg RA.
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
Rich66 is offline   Reply With Quote
Old 10-21-2009, 04:40 PM   #45
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

1: AAPS J. 2009 Oct 20. [Epub ahead of print]
MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications.

Desano JT, Xu L.
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
Rich66 is offline   Reply With Quote
Old 10-28-2009, 03:55 PM   #46
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?



Stem Cell Therapies Aimed at Patient Trials Get $230 Million
Share | Email | Print | A A A


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, the agency’s president. The top-ranked project is a partnership of the City of Hope, a nonprofit treatment center near Los Angeles, and Sangamo Biosciences, 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.
$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, 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 in San Francisco at rwaters5@bloomberg.net.
Last Updated: October 28, 2009 14:49 EDT





Terms of Service | Privacy Policy | Trademarks
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 10-30-2009, 11:48 PM   #47
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

Nippon Rinsho. 2009 Oct;67(10):1863-7.
[Cancer stem cell concepts--lesson from leukemia]

[Article in Japanese]
Nitta E, Suda T.
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]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-01-2009, 03:09 PM   #48
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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 organ1, 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 differences2, 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 therapy3.
The idea of CSCs as being the source of post-therapeutic tumor recurrence is not a new one4. Indeed, scientists in the late nineteenth century proposed that a rare population of cells with stem-like properties may be the source of tumors5-7. As technologies improved, people began noticing that cancers contained cells that differed in their abilities to proliferate in colony formation assays8 and spleen repopulation assays9-11, 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 198812. More recently, Bonnet and Dick13 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 cannot4,14,15. The most substantiated CSC selection methods have been developed for leukemias13, central nervous system tumors including glioma16-20, and breast cancer21, but similar selection techniques appear to be applicable to other tumors, with accumulating evidence for existence of a CSC subpopulation in tumors of the colon22,23, pancreas24, prostate25, melanoma26, liver27 and head and neck28.
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 glioblastomas29, 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). 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 tumorigenesis30,31. 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.



Figure 1CSC-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 ...)



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 cells32. 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+ 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 line33. In this system, overexpression of β-catenin in the Sca+ 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+ 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 al29. Normal stem cells activate the Wnt/β-catenin signalling axis during development34, 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 pathway35. 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 cancer36 and may promote conversion of non-tumorigenic stem cells to glioma CSCs through the destabilization of the genome37. 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.38 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 therapy39. 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 bulk40,41 and a dominant negative form of EGFR can enhance radiosensitivity in glioma cell lines42. 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 instability43.



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 vivo44. Recent data suggests that preferential Akt activity may confer chemotherapy resistance to hepatocellular carcinoma CSCs45. One group found that CSCs from gliomas display marked resistance to several chemotherapeutic agents (temozolamide, carboplatin, VP16 and Taxol) relative to the non-CSC population46. 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 phenotype47 and could be manipulated in efforts to sensitize CSCs to cytotoxic chemotherapies (Figure 1c, d).
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 cells48, and stem-like neuroblastoma cells displayed a similar ability to pump mitoxantrone, resulting in increased cell survival49. 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 vinblastine50 and paclitaxel51, while BCRP prevents accumulation of imatinib mesylate52, topotecan53 and methotrexate54.
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 cells55. ALDH1 activity is amplified in leukemic CSCs and thus may have implications for the resistance of these cells to chemotherapeutic agents such as cyclophosphamide56. ALDH1 is expressed by breast CSCs and is associated with a poor prognosis57 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 quiescent58,59, 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 cancers60. Anti-angiogenic agents such as bevacizumab (Avastin) have shown promise as part of a combination therapy regimen in several advanced cancers, including colon cancer61 and glioblastoma62. 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 secretion60. 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 drugs63. 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 vitro64. 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 tumors65.
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.66 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 2a). In this way, CSCs mimic normal stem cells, which also seem to be dependent on vascular niches and factors secreted by the vasculature67,68. Factors like leukaemia inhibitory factor (LIF), brain derived neurotrophic factor (BDNF) and pigment epithelial derived factor (PEDF) have been implicated in normal stem cell maintenance67, 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 2b).



Figure 2Anti-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 ...)



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 survival69. These complex effects on radiation sensitivity have not yet been dissected, but we have noted that irradiated CSC-derived tumors are particularly vascular and hemorrhagic29, 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 conditions70, 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 radiation71-73. 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 Pten74. The authors demonstrate that while the CSCs and the resultant leukemias are effectively treated by rapamycin treatment, the proliferation of non-cancerous Pten−/− 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. 2009 Dec 15;106(50):21306-11. Epub 2009 Dec 2.
Human cancers converge at the HIF-2{alpha} oncogenic axis.

Franovic A, Holterman CE, Payette J, Lee S.
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]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-04-2009, 11:20 AM   #49
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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.



-----------
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.
Attached Files
File Type: pdf Resistance to Endocrine Therapy_Breast CSC.pdf (214.5 KB, 191 views)
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-08-2009, 01:29 PM   #50
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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.
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-08-2009, 11:34 PM   #51
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

Cancer Immunol Immunother. 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, Matsueda S, Li Y, Tokumitsu H, Gao H, Danes C, Wong KK, Wang X, Ferrone S, Ioannides CG.
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.
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-09-2009, 12:19 AM   #52
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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


Full text: http://www.nature.com/onc/journal/v2...c2008207a.html

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

H Korkaya1, A Paulson1, F Iovino1,2 and M S Wicha1
1Department 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
2Current 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 pageAbstract

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.
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-10-2009, 03:55 PM   #53
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

Biol Cell. 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, Kao AP, Chang CC, Lee JN, Chai CY, Hou MF, Liu CM, Tsai EM.
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]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-15-2009, 04:30 PM   #54
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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.
Copyright 2009 News-Letter



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


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."










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

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-15-2009, 06:00 PM   #55
bejuce
Senior Member
 
bejuce's Avatar
 
Join Date: May 2009
Posts: 510
Re: Cancer stem cells: The root of all evil?

"...could one day eliminate cancer recurrence." I like that! And hope this day is closer than we think!
__________________
ER+ (30%)/PR-/HER-2+, stage 3

Diagnosed on 02/18/09 at 38 with a huge 12x10 cm tumor, after a 6 month delay. Told I was too young and had no risk factors. Found swollen node during breastfeeding.
March-August 09: neo-adjuvant chemo, part of a trial at Stanford (4 DD A/C, 4 Taxotere with daily Tykerb), loading dose of Herceptin
08/12/09 - bye bye boobies (bilateral mastectomy)
08/24/09 - path report shows 100 % success in breast tissue (no cancer there, yay!), 98 % success in lymphatic invasion, and even though 11/13 nodes were still positive, > 95 % of the tumor in them was killed. Hoping for the best!
September-October 09: rads with daily Xeloda
02/25/10 - Cholecystectomy
05/27/10 - Bone scan clear
06/14/10 - CT scan clear, ovarian cyst found
07/27/10 - Done with Herceptin!
02/15/11 - MVA-BN HER-2 vaccine trial
03/15/11 - First CA 15-3: 12.7 and normal, yay!
10/01/11 - Bone scan and CT scan clear, fatty liver found
now on Tamoxifen and Aspirin


bejuce is offline   Reply With Quote
Old 01-22-2010, 04:28 PM   #56
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Cancer stem cells: The root of all evil?

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


E-mail | Print | 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/b...stem-cell.html



Clinical Study

British Journal of Cancer (2010) 102, 815–826. doi:10.1038/sj.bjc.6605553 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 Nakanishi1,5, S Chumsri1, N Khakpour1, A H Brodie1, B Leyland-Jones2, A W Hamburger1, D D Ross1,3 and A M Burger4
  1. 1Departments of Medicine, Pathology, Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Cancer Center (UMGCC), Baltimore, MD, USA
  2. 2Department of Hematology and Medical Oncology, Winship Cancer Center, Emory University, Atlanta, GA, USA
  3. 3Baltimore VA Medical Center, Baltimore, MD, USA
  4. 4Barbara 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
5Current 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 pageAbstract

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 (r2=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
__________________

Mom's treatment history (link)
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 10:40 PM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2020, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007
free webpage hit counter