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Are Cancer Stem Cells Ready for Prime Time?

A flood of new discoveries has refined our definition of cancer stem cells. Now it’s up to human clinical trials to test if they can make a difference in patients.

By | April 1, 2012

PHOTO RESEARCHERS, INC., DAVID MCCARTHY

In the 30-year battle waged since the initiation of the “war on cancer,” there have been substantial victories, with cures for childhood malignancies among the most important. Our ever-expanding understanding of cellular and molecular biology has provided substantial insights into the molecular underpinnings of the spectrum of diseases we call cancer. Yet, while researchers view this as tremendous progress, many patients have seen only limited improvement. In fact, the relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.[1. C. Leaf, “Why we’re losing the war on cancer (and how to win it),” Fortune, 149:76-82, 84-86, 88 passim., 2004.]

Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemy—the cancer stem cell. Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease.

The idea that cancers are driven by cells with “embryonic features” is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ.

A number of groups, including our own, have identified cancer stem cell markers enabling the isolation and characterization of these cells. In addition, the development of in vitro and mouse functional assays has led to a veritable explosion of research on cancer stem cells from both blood-derived malignancies and solid tumors.[2. A. Larochelle et al., “Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy,” Nat Med, 2:1329-37, 1996.],[3. M. Al-Hajj et al., “Prospective identification of tumorigenic breast cancer cells,” PNAS, 100:3983-88, 2003.] However, the limitations of these markers and assays have generated heated debate regarding which tumors follow a stem cell model, and which do not. New data from our lab and from others is helping to clarify some of these areas of debate with the goal of better understanding how these cells can be identified and characterized.

Clarifying the debate

A cancer stem cell (CSC) is defined as a cell that has the ability to self-renew, dividing to give rise to another malignant stem cell, as well as to produce the phenotypically diverse, differentiated tumor cells that form the bulk of the tumor. Evidence for CSCs was first documented in leukemia, where it was clear that only a small subset of cancer cells was capable of perpetuating the cancer upon serial transplantation from one mouse to another. Extensive knowledge of normal blood stem cells facilitated our recognition and understanding of leukemia stem cells. Evidence for CSCs in solid tumors has been more controversial, because it is more technically challenging to divide a solid mass into individual cells without damage or alteration, and knowledge of the properties of normal-tissue stem cells in these organs is more limited. However, some of the areas of contention may be resolved by continuing research into the biology of these CSCs.

Relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.

One of the points of confusion in CSC biology is the question of where these cells come from. Do they arise from normal stem cells that have become cancerous through mutation, or do they arise from partially differentiated tissue-progenitor cells that have acquired the ability to self-renew? Recent evidence suggests CSCs may arise from either source.

A second misconception is that the definition of CSCs precludes the possibility that cancers arise from sequential mutations that accumulate over many cell generations and are selected for through a Darwinian process—the so-called “clonal evolution model.” Some have proposed that the “CSC model” is a competing theory of carcinogenesis. In fact, both models may be correct. There is evidence that CSCs may also be genetically unstable, resulting in clonal evolution that generates several distinct CSC clones in a tumor.

While the identification of CSC markers and the development of in vitro and mouse models have led to important advances in the field, each of these markers and models has limitations that have fueled debate. Markers used to isolate cancer stem cells, such as CD44, CD24, CD133, aldehyde dehydrogenase (ALDH), and Hoechst dye exclusion, have proven useful for identifying these cell populations in tumor samples. However, expression of these markers is highly dependent on experimental conditions such as culture medium and oxygen concentration. Similarly, in vitro assays that rely on the ability to form spherical colonies in suspension can be useful, but are notoriously inaccurate. Since the definition of CSCs is ultimately an operational one, the most reliable assay for these cells has been their ability to initiate tumors when transplanted into mouse models. Because the immune system will reject any implanted foreign tissue, researchers have had to use immunosuppressed mice to test for human CSCs. In some tumor types, such as melanoma, the proportion of cells capable of initiating tumors is dependent on the degree of immunosuppression in the mouse models utilized. However, the more immunosuppressed mouse models may actually overestimate the true frequency of CSCs.

Recent studies have indicated that CSCs have the ability to evade immune surveillance, even when the same immune cells can detect and destroy bulk tumor cells. If this is truly the case, then highly immunosuppressed models of cancer may not reliably simulate the behavior of the immune system in the microenvironment of a patient’s tumor. Indeed, CSCs isolated from transgenic mouse tumors have been transplanted successfully into mice with intact immune systems, demonstrating the existence of CSCs and providing further support for relevance of these cells in patients.

Another misconception is that the cancer stem cell hypothesis requires that CSCs be rare. In fact, studies suggest that the percentage of CSCs may vary significantly in different types of cancer, as well as within each cancer type. In acute leukemia, CSCs appear to be rare, constituting less than 0.1 percent of the total cancer cell population. In some solid tumors, such as breast cancer, their numbers are reported to represent approximately 1–10 percent, while in some tumors, such as melanoma, they may be even more common, leading some investigators to propose that some cancers follow a stem cell model while others don’t. While this is debatable, identifying populations of CSCs in tumors in which these cells are abundant, or in the majority, may be of less importance, since any effective therapy would primarily target the CSCs.

Developmentally informed

Some researchers have focused on defining CSCs from a genetic and developmental perspective. Researchers including Robert Weinberg and colleagues from the Whitehead Institute for Biomedical Research have noted that when cancer cells adopt a genetic program responsible for the epithelial-to-mesenchymal transition (EMT), they convert to a CSC phenotype.[4. S.A. Mani et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, 133:704-15, 2008.] EMT is known to developmental biologists as the transition from a non-motile, epithelial-like cell to one that can detach from the surrounding tissue and migrate. Cellular migration is important in development, and it is also a defining characteristic of aggressive tumors that metastasize to new sites in the body. Both inflammatory immune responses and a hypoxic tumor microenvironment induce EMT in cancers. It is also increasingly recognized that EMT plays an important role in therapeutic resistance.[5. S. Liu et al., “Role of microRNAs in the regulation of breast cancer stem cells,” J Mammary Gland Biol Neoplasia, DOI: 10.1007/s10911-012-9242-8, 2012.]

Infographic: The Two Faces of Metastasis  View full size JPG | PDF
Infographic: The Two Faces of Metastasis
View full size JPG | PDF
HARRY CAMPBELL

In contrast, other studies have suggested that the EMT state, although associated with tumor invasion, is characterized by cellular quiescence, or an inability to replicate, creating a paradox. How can cells which are associated with aggressive metastatic behavior be quiescent? Recent observations by our group and others have suggested an additional mechanism that could explain both observations: CSCs may in fact flip-flop between an EMT state and its converse, the mesenchymal-to-epithelial transition (MET), in which cells re-attach to the matrix and become highly proliferative, thus generating tumors at sites of metastasis.

These results suggest that CSCs, such as those found in breast cancers, have plasticity and can exist in two alternative states: an EMT-like state of CSCs expressing surface markers CD44 but not CD24 (CD44+CD24), and an MET-like population expressing the CSC marker ALDH. Previous studies taken together with our current work suggest that CSCs located inside the primary tumor mass exist predominantly in the MET state in which they are highly proliferative and express ALDH. In contrast, tumor cells that migrate into the circulation and metastasize are characterized as CD44+CD24—highly invasive but quiescent EMT CSCs.5 This scenario is supported by studies showing that in women with breast-cancer-derived, bone micrometastases express the EMT CSC markers CD44+CD24.5 These micrometastases are largely quiescent, as indicated by their lack of expression of markers of cellular proliferation such as Ki67.5 In order to enter a proliferative state, EMT CSC cells must undergo an MET transition in which they lose their invasive characteristics and acquire self-renewal capacity.

Clinical implications of cancer stem cell models

The effectiveness of the majority of cancer chemotherapeutic agents has been judged by their ability to cause tumor regression, as ascertained by direct measurement or through radiographic imaging. Since tumor size is largely determined by bulk cell populations, however, it follows that tumor regression reflects changes in this population rather than in the rarer CSCs, which may be the real drivers of tumor growth and metastasis. This could explain why in many cancers tumor regression does not translate to increased patient survival. There is substantial evidence in preclinical models that most CSCs are relatively resistant to chemotherapeutic agents and radiation therapy. In addition, CSCs may display resistance to molecularly targeted therapeutics. For example, one of the greatest advances within targeted therapeutics has been the development of imatinib (Gleevec) for chronic myelogenous leukemia (CML). Almost all patients treated with this molecularly targeted tyrosine kinase inhibitor enter clinical remission. However, disease quickly recurs following discontinuation of the drug, and CML cancer stem cells have been demonstrated to be resistant to this agent. This has led to experimental approaches that target CSCs using agents such as sirtuin inhibitors[6. L. Li et al., “Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib,” Cancer Cell, 21:266-81, 2012.] or interferon.

Another targeted therapy is trastuzumab (Herceptin), the development of which has represented a major advance in therapy for breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Unfortunately, only some 20 percent of women with breast cancer have this genetic alteration. In 2008, however, researchers from the University of Pittsburgh published clinical trial results showing that women who were HER2-negative also appeared to benefit from treatment when the drug was part of the chemotherapy cocktail given after surgery to prevent recurrence. This puzzling finding could have huge implications for the majority of breast cancers that are currently not being treated with the drug. When we looked further into HER2 expression patterns, we found that this receptor also increased the self-renewal of breast CSCs.[7. H. Korkaya et al., “HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion,” Oncogene, 27:6120-30, 2008.] This may provide an explanation for the remarkable efficacy of the drug, which blocks HER2.[8. S. Paik et al., “HER2 status and benefit from adjuvant trastuzumab in breast cancer,” N Engl J Med, 358:1409-11, 2008.] Our ongoing preclinical studies indicate that trastuzumab can kill the CSCs in tumors that express this receptor only on their CSCs, and would thus be classified as HER2-negative.[9. S. Liu, M.S. Wicha “Targeting breast cancer stem cells,” J Clin Oncol, 25:4006-12, 2010.]

New Horizon for Cancer Treatment

The cancer stem cell (CSC) hypothesis offers explanations for many of the frustrating failures of cancer therapy in the clinic. The resistance of CSCs to chemotherapy, radiation, and many targeted therapies, may explain why cancers come back after the tumor mass has been removed and the patient has gone into remission. As such, CSCs offer a new target for attack.

Chemo catch-22:Although chemotherapy is still considered to be the most effective treatment for many cancers, the drugs may act on a tumor’s surrounding tissue in a way that spurs the production of more stem cells. In fact, increases in CSC numbers have been observed in tumors after chemo or radiation. These treatments can create inflammation in the tissue surrounding the tumor as well as hypoxia, or loss of oxygen, which activates Wnt signaling. Inflammatory mediators such as IL-8, IL-6, and Wnt signaling spur CSCs to self-renew or increase in number, thus driving tumor growth.

Antiangiogenic agents are another treatment whose administration may need to be rethought in light of what we now know about CSC biology. The development of antiangiogenic agents such as bevacizumab (Avastin) and sunitinib (Sutent) represented an area of significant promise in cancer. However, recent clinical trials have produced relatively disappointing results. Although these agents delay tumor progression, they do not significantly increase patient survival. Our group has demonstrated that in mouse models, these antiangiogenic agents actually increase CSC populations through generation of tumor hypoxia, or low oxygenation,which drives the proliferation of CSCs by triggering the Akt and Wnt pathways.[10. S.J. Conley et al., “Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia,” PNAS, 109:2784-89, 2012.] This suggests that, to be clinically effective, these agents may require additional therapies capable of targeting CSC populations.

Over the past decade, a number of developmental pathways that regulate the self-renewal of normal stem cells have been elucidated. These include the developmental pathways Wnt, Notch, and Hedgehog, and the cell division and proliferation pathways PI-3K, NF-kB and Jak/STAT. Interestingly, these pathways are dysregulated in many human cancers, leading to uncontrolled self-renewal of CSCs.[11. H. Korkaya et al., “Breast cancer stem cells, cytokine networks, and the tumor microenvironment,” J Clin Invest, 121:3804-09, 2011.] These pathways may provide excellent targets for developing drugs against CSCs.

In addition to the regulation of CSCs by intrinsic signals, elements in the tumor microenvironment or niche also play a role in regulation of the stem cells. In tumors, this niche contains a variety of cellular elements, including inflammatory cells, fibroblasts, endothelial cells, and mesenchymal stem cells.[12. A. Albini, M.B. Sporn, “The tumour microenvironment as a target for chemoprevention,” Nat Rev Cancer, 7:139-47, 2007.] Iterative crosstalk between cancer stem cells, their differentiated progeny, and the microenvironment regulates cellular function through paracrine cell signaling. Some of these interactions include the Wnt, Notch, and Hedgehog pathways. In addition, inflammatory cells, fibroblasts, and mesenchymal stem cells may interact with CSCs and increase their production and replication via cytokine loops. Several inflammatory cytokines, including IL-6 and IL-8, have been demonstrated to increase breast cancer stem cell self-renewal in mouse models and in vitro. In addition, chemotherapy-induced cellular toxicity increases local IL-8 production, which may contribute to increased cancer stem cell populations following chemotherapy. High serum levels of IL-6 and IL-8 in patients with advanced breast cancers have been associated with development of metastasis and poor outcome.11 These studies suggest that developing strategies to interfere with these loops may provide a novel way to target CSCs. Interestingly, statins, which have anti-inflammatory effects, have been reported to decrease breast cancer risk.[13. R. Kochhar et al.,”Statins reduce breast cancer risk: a case control study in US female veterans,” J Clin Oncol, ASCO Annual Meeting Proceedings 23:514, 2005.]

We have also recently demonstrated that blocking IL-8 with antibodies or drugs targets breast CSCs in mouse models and inhibits tumor growth and metastasis.11 Repertaxin, a drug that blocks the IL-8 receptor, was developed to prevent graft rejection and has been reported to be relatively nontoxic in phase I clinical trials. We have recently begun a clinical trial combining Repertaxin with chemotherapy in women with advanced breast cancer.

In the past 5 years there has been an exponential increase in CSC research. This research has helped to resolve a number of controversies regarding identification of these cells and their role in driving tumor growth and mediating treatment resistance. Despite these advances, the CSC field is still in its relative infancy, and many questions and challenges remain. More than a dozen biotechnology and pharmaceutical companies are now vigorously pursuing CSC research. As a result, a number of early-phase clinical trials targeting CSCs are in progress. These studies and the later-stage efficacy trials that follow them should indicate whether successful targeting of CSCs significantly improves outcomes in cancer patients. If this is found to be the case, it may usher in the beginning of a new era of cancer therapy.

Suling Liu, Hasan Korkaya, and Dr. Max S. Wicha, Director, UM Cancer Center, are all at the University of Michigan Comprehensive Cancer Center.

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Avatar of: azar123

azar123

Posts: 11

April 3, 2012

 

CSC is most probably a non existing definition myth,
propagated by interested group of researchers and industry never been isolated
and defined by non specific markers . Stem
cells by definition are pleiotropic (they can become any type of cell) and CSC are NOT. A breast cancer stem
cell cannot be converted to melanoma or testicular cancer cells.

Avatar of: azar123

azar123

Posts: 11

April 3, 2012

NO! 

CSC is most probably a non existing definition myth,
propagated by interested group of researchers and industry never been isolated
and defined by non specific markers . Stem
cells by definition are pleiotropic (they can become any type of cell) and CSC are NOT. A breast cancer stem
cell cannot be converted to melanoma or testicular cancer cells.

Avatar of: azar123

azar123

Posts: 11

April 3, 2012

 

CSC is most probably a definition myth, propagated by
interested group of researchers and industry. Stem cells by definition are pleiotropic (they can become any type
of cell) and CSC are NOT. A breast
cancer stem cell cannot be converted to melanoma or testicular cancer cells

Avatar of: Hasan Korkaya

Hasan Korkaya

Posts: 1457

April 3, 2012

Don't you think the concept deserves to be investigated 
what if it may explain the the failure of current treatment approach of advanced/metastatic cancers which did not improve in the last 30 years 

Avatar of: Paul Knoepfler

Paul Knoepfler

Posts: 1457

April 3, 2012

Thanks for the very comprehensive and insightful review. There are many shared aspects of molecular machinery between cancer stem cells and pluripotent stem cells.
Paul
http://www.ipscell.com

Avatar of:

Posts: 0

April 3, 2012

Thanks for the very comprehensive and insightful review. There are many shared aspects of molecular machinery between cancer stem cells and pluripotent stem cells.
Paul
http://www.ipscell.com

Avatar of:

Posts: 0

April 3, 2012

 

CSC is most probably a definition myth, propagated by
interested group of researchers and industry. Stem cells by definition are pleiotropic (they can become any type
of cell) and CSC are NOT. A breast
cancer stem cell cannot be converted to melanoma or testicular cancer cells

Avatar of:

Posts: 0

April 3, 2012

Don't you think the concept deserves to be investigated 
what if it may explain the the failure of current treatment approach of advanced/metastatic cancers which did not improve in the last 30 years 

Avatar of:

Posts: 0

April 3, 2012

 

CSC is most probably a non existing definition myth,
propagated by interested group of researchers and industry never been isolated
and defined by non specific markers . Stem
cells by definition are pleiotropic (they can become any type of cell) and CSC are NOT. A breast cancer stem
cell cannot be converted to melanoma or testicular cancer cells.

Avatar of:

Posts: 0

April 3, 2012

NO! 

CSC is most probably a non existing definition myth,
propagated by interested group of researchers and industry never been isolated
and defined by non specific markers . Stem
cells by definition are pleiotropic (they can become any type of cell) and CSC are NOT. A breast cancer stem
cell cannot be converted to melanoma or testicular cancer cells.

Avatar of:

Posts: 0

April 4, 2012

it is kind of sad how little understanding of the issues immediately becomes an opportunity to invoke conspiracies by those who do all this hard work (as if we had the time to waste on such endeavors)..obviously the notion of cancer stem cell applies to the cancer in which it is found, in which cell division has an asymmetric result: one of the daughter cells will be different, which is the definition of a stem cell in a differentiated tissue..the pleiotropic nature of stem cells in only expressed in embryonic totipotent cells..

Avatar of:

Posts: 0

April 4, 2012

Ron, if you cite the paper of Chao et al in Cancer Res 2011, at
least have the intellectual honesty to be accurate they have determined that  “Significantly, anti-CD47 antibody
eliminated ALL in the peripheral blood, bone marrow, spleen, and liver of mice
engrafted with primary human ALL. These data provide preclinical support for
the development of an anti-CD47 antibody
therapy for treatment of human ALL.â€쳌 Nothing about other tumors and CD47is not
a  CSC marker, there is not  such thing as a CSC specific marker, since maybe
on a good day an over expressed proteins on some cells. May be perceived as a
hint of a marker by the field followers. Interested  scientist and industry are trying to claim a
fame and fortune on an attractive definition of non-existing non-proven
biological phenomenon. NOBODY was able to isolate CSC and prove without a
shadow of a doubt that they even exist. Fooling the patients population is unethical
and we all going to pay the price for some charlatans.

Avatar of:

Posts: 0

April 4, 2012

Perhaps azar 123 might consider that the definition of stem cells could be broadened to include cancer stem cells.
Stamford Uni Med Center has just published that blood cancer stem cells overexpress a protein CD47 as do a range of solid human tumors.
Treatment with an antibody to CD47 has prevented metastasis and caused a range of transplanted solid human tumors to regress.

Avatar of:

Posts: 0

April 4, 2012

Good question! In fact, the CSC currently studied in some experiments are not real or pure CSC. rather ligenage-specific cancer propagating progenitor cells (>1% up to 50% in cancer) or a mixture. Also, the concept of CSC need to be more pricisely defined. CSC theory should be able to explain its association with whole process of tumor development. Thus, current concept of CSC only represent a subset of tumor stem cell (TSC). Early stages of TSC may include tumor-initiating stem cell (TISC) or Cell of origin in cancer, precancerous stem cells (pCSC) and true CSC。 The “CSC" currently used may be a mixture of different stages of TSC.

Avatar of: RonHorgan

RonHorgan

Posts: 8

April 4, 2012

Perhaps azar 123 might consider that the definition of stem cells could be broadened to include cancer stem cells.
Stamford Uni Med Center has just published that blood cancer stem cells overexpress a protein CD47 as do a range of solid human tumors.
Treatment with an antibody to CD47 has prevented metastasis and caused a range of transplanted solid human tumors to regress.

Avatar of: JXG

JXG

Posts: 9

April 4, 2012

Good question! In fact, the CSC currently studied in some experiments are not real or pure CSC. rather ligenage-specific cancer propagating progenitor cells (>1% up to 50% in cancer) or a mixture. Also, the concept of CSC need to be more pricisely defined. CSC theory should be able to explain its association with whole process of tumor development. Thus, current concept of CSC only represent a subset of tumor stem cell (TSC). Early stages of TSC may include tumor-initiating stem cell (TISC) or Cell of origin in cancer, precancerous stem cells (pCSC) and true CSC。 The “CSC" currently used may be a mixture of different stages of TSC.

Avatar of: andras48

andras48

Posts: 2

April 4, 2012

it is kind of sad how little understanding of the issues immediately becomes an opportunity to invoke conspiracies by those who do all this hard work (as if we had the time to waste on such endeavors)..obviously the notion of cancer stem cell applies to the cancer in which it is found, in which cell division has an asymmetric result: one of the daughter cells will be different, which is the definition of a stem cell in a differentiated tissue..the pleiotropic nature of stem cells in only expressed in embryonic totipotent cells..

Avatar of: azar123

azar123

Posts: 11

April 4, 2012

Ron, if you cite the paper of Chao et al in Cancer Res 2011, at
least have the intellectual honesty to be accurate they have determined that  “Significantly, anti-CD47 antibody
eliminated ALL in the peripheral blood, bone marrow, spleen, and liver of mice
engrafted with primary human ALL. These data provide preclinical support for
the development of an anti-CD47 antibody
therapy for treatment of human ALL.â€쳌 Nothing about other tumors and CD47is not
a  CSC marker, there is not  such thing as a CSC specific marker, since maybe
on a good day an over expressed proteins on some cells. May be perceived as a
hint of a marker by the field followers. Interested  scientist and industry are trying to claim a
fame and fortune on an attractive definition of non-existing non-proven
biological phenomenon. NOBODY was able to isolate CSC and prove without a
shadow of a doubt that they even exist. Fooling the patients population is unethical
and we all going to pay the price for some charlatans.

Avatar of:

Posts: 0

April 11, 2012

 Please name a single shared machinery unique to both cell types? You can be assured there are none,  and propagating a myth is deceitful.

Avatar of: azar123

azar123

Posts: 11

April 11, 2012

 Please name a single shared machinery unique to both cell types? You can be assured there are none,  and propagating a myth is deceitful.

Avatar of:

Posts: 0

April 12, 2012

azar123 is confusing embryonic stem cells which are pleiotropic with stem cells in general, which are not necessarily completey pleiotropic. For example, most adult stem cells can differentiate into only a limited number of types of cells. Hemopoietic  stem cells in bone marrow give rise to the various blood cells, but are not broadly pleotropic, for example. So the concept of stem cell includes cells which give rise to a limited number of phenotypes and certainly would include the cells described in this article

Avatar of: Robert Graham

Robert Graham

Posts: 1

April 12, 2012

azar123 is confusing embryonic stem cells which are pleiotropic with stem cells in general, which are not necessarily completey pleiotropic. For example, most adult stem cells can differentiate into only a limited number of types of cells. Hemopoietic  stem cells in bone marrow give rise to the various blood cells, but are not broadly pleotropic, for example. So the concept of stem cell includes cells which give rise to a limited number of phenotypes and certainly would include the cells described in this article

Avatar of: Shabu Shaik

Shabu Shaik

Posts: 1457

April 12, 2012

*To understand the mechanism of signaling pathways important for cancer stem cells functions and the one which facilitate the epithelial to mesenchymal transition in the early phase of cancer metastasis.
*. To understand the mechanisms underlying pre-metastasis niche formation and to target the seeding of CSCs into niche by blocking the regulatory factors for this process keeping in mind side effects of such blockage.
* Develop a novel therapy that targets the cancer stem cells in such a way that inhibits their signaling or pathways regulating self renewal or the invasive ability of CSCs selectively by sparing the normal stem cells. A combination therapy approach might be used

Avatar of: Shabu Shaik

Shabu Shaik

Posts: 1457

April 12, 2012

*.To understand the mechanism of signaling pathways important for cancer stem cells functions and the one which facilitate the epithelial to mesenchymal transition in the early phase of cancer metastasis.
*. To understand the mechanisms underlying pre-metastasis niche formation and to target the seeding of CSCs into niche by blocking the regulatory factors for this process keeping in mind side effects of such blockage.
*. Develop a novel therapy that targets the cancer stem cells in such a way that inhibits their signaling or pathways regulating self
renewal or the invasive ability of CSCs selectively by sparing the normal stem cells. A combination therapy approach might be used

Avatar of:

Posts: 0

April 12, 2012

*To understand the mechanism of signaling pathways important for cancer stem cells functions and the one which facilitate the epithelial to mesenchymal transition in the early phase of cancer metastasis.
*. To understand the mechanisms underlying pre-metastasis niche formation and to target the seeding of CSCs into niche by blocking the regulatory factors for this process keeping in mind side effects of such blockage.
* Develop a novel therapy that targets the cancer stem cells in such a way that inhibits their signaling or pathways regulating self renewal or the invasive ability of CSCs selectively by sparing the normal stem cells. A combination therapy approach might be used

Avatar of:

Posts: 0

April 12, 2012

*.To understand the mechanism of signaling pathways important for cancer stem cells functions and the one which facilitate the epithelial to mesenchymal transition in the early phase of cancer metastasis.
*. To understand the mechanisms underlying pre-metastasis niche formation and to target the seeding of CSCs into niche by blocking the regulatory factors for this process keeping in mind side effects of such blockage.
*. Develop a novel therapy that targets the cancer stem cells in such a way that inhibits their signaling or pathways regulating self
renewal or the invasive ability of CSCs selectively by sparing the normal stem cells. A combination therapy approach might be used

Avatar of: RonHorgan

RonHorgan

Posts: 8

April 13, 2012

Azar 123,
 In your zeal for what may be "scientific purity" you are imputing base motives to several people whom you dont know.
This can be damaging in ways that you may not have considered.
The very thoughtful review paper that asked"Are cancer Stem cells ready for prime time?" obviously required much work. If the authors are criticized harshly they may become disheartened and possibly even quit the field?
We only progress when someone is brave enough to think differently about an old problem.
The enemy is cancer, not people working with a promising new concept that seems to have really good potential.
Do you really think that researchers in this field are self interested  charlatans?
I have talked with terminal cancer patients and post mortem analyzed their organs to determine drug distribution.
My rewards were not financial, and my motives altruistic, as I would expect is typical of  most people who choose such grueling work.
You accuse me of intellectual dishonesty on the assumption that I have commented on the Chao paper.
The reference was to Edris et al Proc. Nat.Acad Sci Mar 26 2012.
Anonymous comment is .......

Avatar of: azar123

azar123

Posts: 11

April 13, 2012

Altruism, no interest in salary, patents, meeting invitation etc.? Give me a brake, instead please go help inner city kids or work at a disaster strike zone instead.
You are providing nothing but a veil emotional argument which lacks a single scientific evidence that “cancer stem cellsâ€쳌 do exist, I wish they would as it might will makes my life and others much easier and probably longer.
It is nothing but Cancer Flavor of the Day, and like many flavors propagated by interested scientists and the pharmaceutical industry it will also pass and join the grave yard of false hopes, while crushing the hope of the patients for the elusive “New Treatment/Cureâ€쳌 .

Lastly, let me re fraise the Simpsons as it seems that you hold the same philosophy
â€쳌 if it sounds good it is good for you â€쳌

Altruism, no interest in salary, patents, meeting invitation
etc.? Give me a brake, instead please go help inner city kids or disaster strike
zones instead.   

You are providing nothing but   veil emotional
arguments without a shred of a single scientific evidence that  “cancer stem cellsâ€쳌  do exist, I wish they would it will make my
life and others much easier and probably longer.

It only sound good and it is the Cancer Flavor of the Day,
and like many flavors res propagated by interested scientists and the pharmaceutical
industry it will also pass, and the hope of the patient for the elusive “New
Treatmentâ€쳌 will be crushed again.

Lastly, let me re fraise the Simpsonsâ€쳌 if it sounds good it
is  good for you â€쳌

Avatar of: azar123

azar123

Posts: 11

April 13, 2012

 

Regrettably you mislead the public again and  the paper 
of Edris et al does no deal with CSC but with  leiomyosarcoma. Some of us know how to search
and reveal if a claim is genuine or an unsubstantiated affirmation and yours  is the latter.

The paper concludes “In conclusion, we have found that CD47
is expressed on LMS tumor cells and we have demonstrated that inhibiting CD47
function using monoclonal antibodies is an effective method of treating LMS
tumors in vitro and in vivo, thereby forming the rationale for evaluating the
clinical efficacy of anti-CD47 therapy in human patients with LMS tumors.
Further studies are needed to address the relationship between the density of
TAMs and the efficacy of anti-CD47 treatment in LMS, and subsequently to
explore the possibility of combining anti-CD47 mAb therapy with treatments that
modulate the CSF1 pathway in order harness TAMs as biological tools to decrease
tumor growth in patients with LMSâ€쳌.

 Enough said

Avatar of:

Posts: 0

April 13, 2012

Azar 123,
 In your zeal for what may be "scientific purity" you are imputing base motives to several people whom you dont know.
This can be damaging in ways that you may not have considered.
The very thoughtful review paper that asked"Are cancer Stem cells ready for prime time?" obviously required much work. If the authors are criticized harshly they may become disheartened and possibly even quit the field?
We only progress when someone is brave enough to think differently about an old problem.
The enemy is cancer, not people working with a promising new concept that seems to have really good potential.
Do you really think that researchers in this field are self interested  charlatans?
I have talked with terminal cancer patients and post mortem analyzed their organs to determine drug distribution.
My rewards were not financial, and my motives altruistic, as I would expect is typical of  most people who choose such grueling work.
You accuse me of intellectual dishonesty on the assumption that I have commented on the Chao paper.
The reference was to Edris et al Proc. Nat.Acad Sci Mar 26 2012.
Anonymous comment is .......

Avatar of:

Posts: 0

April 13, 2012

Altruism, no interest in salary, patents, meeting invitation etc.? Give me a brake, instead please go help inner city kids or work at a disaster strike zone instead.
You are providing nothing but a veil emotional argument which lacks a single scientific evidence that “cancer stem cellsâ€쳌 do exist, I wish they would as it might will makes my life and others much easier and probably longer.
It is nothing but Cancer Flavor of the Day, and like many flavors propagated by interested scientists and the pharmaceutical industry it will also pass and join the grave yard of false hopes, while crushing the hope of the patients for the elusive “New Treatment/Cureâ€쳌 .

Lastly, let me re fraise the Simpsons as it seems that you hold the same philosophy
â€쳌 if it sounds good it is good for you â€쳌

Altruism, no interest in salary, patents, meeting invitation
etc.? Give me a brake, instead please go help inner city kids or disaster strike
zones instead.   

You are providing nothing but   veil emotional
arguments without a shred of a single scientific evidence that  “cancer stem cellsâ€쳌  do exist, I wish they would it will make my
life and others much easier and probably longer.

It only sound good and it is the Cancer Flavor of the Day,
and like many flavors res propagated by interested scientists and the pharmaceutical
industry it will also pass, and the hope of the patient for the elusive “New
Treatmentâ€쳌 will be crushed again.

Lastly, let me re fraise the Simpsonsâ€쳌 if it sounds good it
is  good for you â€쳌

Avatar of:

Posts: 0

April 13, 2012

 

Regrettably you mislead the public again and  the paper 
of Edris et al does no deal with CSC but with  leiomyosarcoma. Some of us know how to search
and reveal if a claim is genuine or an unsubstantiated affirmation and yours  is the latter.

The paper concludes “In conclusion, we have found that CD47
is expressed on LMS tumor cells and we have demonstrated that inhibiting CD47
function using monoclonal antibodies is an effective method of treating LMS
tumors in vitro and in vivo, thereby forming the rationale for evaluating the
clinical efficacy of anti-CD47 therapy in human patients with LMS tumors.
Further studies are needed to address the relationship between the density of
TAMs and the efficacy of anti-CD47 treatment in LMS, and subsequently to
explore the possibility of combining anti-CD47 mAb therapy with treatments that
modulate the CSF1 pathway in order harness TAMs as biological tools to decrease
tumor growth in patients with LMSâ€쳌.

 Enough said

Avatar of: kevin

kevin

Posts: 1457

April 16, 2012

...

Avatar of: Bill

Bill

Posts: 1457

April 16, 2012

Shouldn't Wicha disclose that he was a co-founder of OncoMed, a cancer stem cell company?

Avatar of:

Posts: 0

April 16, 2012

...

Avatar of:

Posts: 0

April 16, 2012

Shouldn't Wicha disclose that he was a co-founder of OncoMed, a cancer stem cell company?

Avatar of: Guest

Anonymous

April 19, 2012

 Has anyone asked azar123 to disclose his own credentials and his own accomplishments? 

If azar123 has greater expertise to offer, what is his/her educational history.  What are some of his/her papers, that we might read them and seek to discern whether he/she has something to gain by his/her vitriolic ad hominem assertions. 

Perhaps he/she has done some work of his/her own that would, on its own merits, put to shame what you, or any other commenter here might have accomplished or presently be accomplishing.

(I've never seen students graded harder by anyone than by one associate professor who repeatedly failed to present a dissertation that passed muster.  Do you discern here what might be a whiff of sour grapes, or some such taint of emotional baggage?  What's driving this angst, do you suppose?)

Avatar of: Guest

Anonymous

April 19, 2012

 Ron, you make some arguments that scream to be made amidst the noise.  You are, in my opinion, absolutely correct in saying "We only progress when someone is brave enough to think differently about an old problem.  We may not be so much "losing the battle against cancer," as losing the battle against the boundaries of ritualized convention and resistance to change.  While it is productive to challenge new ideas suggested, new hypotheses to test, alternative interpretations of old findings, it is lethal to creative thinking to attack it as "alien to sound thinking" where currently conceived "sound thinking" is fanning out at the plate or at best hitting pop-ups to the infield.

What I am about to say is not directed toward you, or to anyone doing the s--t work that results in progress toward any scientific goal (such as finding effective, affordable, efficient treatments of cancers.  It is merely to make a general observation that applies to all "reporting" across the board, regardless of the field or the specific issue under study: 

I strongly concur with one commenter's indicating that disclosure and transparency are always vital where there can be even the appearance of a conflict of interest.  If, for example, a writer of a paper has a monetary interest in a company producing a service or product, writes a paper promoting experimentation that applies that service or product, disclosure of that information is in order.  On the other hand, a manager or shareholder in a business providing a given business or service might have superior expertise in that product or service which qualifies him/her by virtue of extensive experience and contemplation and familiarity with that product or service.  Hence he/she may be better qualified than most to discern reasons why that product or service may, indeed, offer great promise.  For another, or others, to point out the writer's vested interest in commercialization of the product or service in subject could, in such a case, attenuate the appearance of possible subjectivity.

In research, full disclosure and transparency are every bit as vital to real progress as are standard accounting procedures in financial statements -- if not moreso.  The avoidance of any appearance of subjectivity is, I would estimate, almost as important as credibility and ethical integrity themselves.  I have argued elsewhere that the more daring a departure is made from conventional thinking and orthodox approach to a study the more essential is clarity of reporting, as to  description of one's rationale in hypothesis derivation, details of what is novel about atypical methodology  explanation of details of results and articulation of ways in which interpretation of results departs from what may be convention thinking among others -- especially the majority of others.  And, full disclosure of any vested interest in any vested interest or potential benefit that even might accrue to the author, if others do pursue a recommended research approach, not only is transparency deserved by others, but should be recognized by others as an indication of good faith.  Even as a victim of cancer would not be wise to doubt an oncologists "vested interest" in earning money by treating cancer patients, neither should any reader doubt the validity of a paper on grounds the writer might, in some way, benefit if the paper generates interest on part of others in pursuing a particular avenue of research. 

If, on the other hand, the author of a paper has nothing (other than recognition for his/her contribution, and concomitant prospects of gaining further research grants) there is no harm in disclosing that, either.

These my comments are in no way meant to apply to any one individual.

You, and others who do the grueling, redundant, often thankless work of testing one idea after another after another, should not be subjected to suggestive innuendo that has potential to do great undeserved harm to you or your efforts.

I merely wish to stress that the author of a paper will always do well to anticipate as much as practical, any factor highly likely to be cited critically against his objectivity unreasonably, as well as reasonably. 

Again, these are GENERAL comments on my part, and not intended toward you or any other person in particular.

May progress be made, and any undeserved nitpicking or innuendo be given no more thought than appropriate to that progress.  

Avatar of:

Posts: 0

April 19, 2012

 Ron, you make some arguments that scream to be made amidst the noise.  You are, in my opinion, absolutely correct in saying "We only progress when someone is brave enough to think differently about an old problem.  We may not be so much "losing the battle against cancer," as losing the battle against the boundaries of ritualized convention and resistance to change.  While it is productive to challenge new ideas suggested, new hypotheses to test, alternative interpretations of old findings, it is lethal to creative thinking to attack it as "alien to sound thinking" where currently conceived "sound thinking" is fanning out at the plate or at best hitting pop-ups to the infield.

What I am about to say is not directed toward you, or to anyone doing the s--t work that results in progress toward any scientific goal (such as finding effective, affordable, efficient treatments of cancers.  It is merely to make a general observation that applies to all "reporting" across the board, regardless of the field or the specific issue under study: 

I strongly concur with one commenter's indicating that disclosure and transparency are always vital where there can be even the appearance of a conflict of interest.  If, for example, a writer of a paper has a monetary interest in a company producing a service or product, writes a paper promoting experimentation that applies that service or product, disclosure of that information is in order.  On the other hand, a manager or shareholder in a business providing a given business or service might have superior expertise in that product or service which qualifies him/her by virtue of extensive experience and contemplation and familiarity with that product or service.  Hence he/she may be better qualified than most to discern reasons why that product or service may, indeed, offer great promise.  For another, or others, to point out the writer's vested interest in commercialization of the product or service in subject could, in such a case, attenuate the appearance of possible subjectivity.

In research, full disclosure and transparency are every bit as vital to real progress as are standard accounting procedures in financial statements -- if not moreso.  The avoidance of any appearance of subjectivity is, I would estimate, almost as important as credibility and ethical integrity themselves.  I have argued elsewhere that the more daring a departure is made from conventional thinking and orthodox approach to a study the more essential is clarity of reporting, as to  description of one's rationale in hypothesis derivation, details of what is novel about atypical methodology  explanation of details of results and articulation of ways in which interpretation of results departs from what may be convention thinking among others -- especially the majority of others.  And, full disclosure of any vested interest in any vested interest or potential benefit that even might accrue to the author, if others do pursue a recommended research approach, not only is transparency deserved by others, but should be recognized by others as an indication of good faith.  Even as a victim of cancer would not be wise to doubt an oncologists "vested interest" in earning money by treating cancer patients, neither should any reader doubt the validity of a paper on grounds the writer might, in some way, benefit if the paper generates interest on part of others in pursuing a particular avenue of research. 

If, on the other hand, the author of a paper has nothing (other than recognition for his/her contribution, and concomitant prospects of gaining further research grants) there is no harm in disclosing that, either.

These my comments are in no way meant to apply to any one individual.

You, and others who do the grueling, redundant, often thankless work of testing one idea after another after another, should not be subjected to suggestive innuendo that has potential to do great undeserved harm to you or your efforts.

I merely wish to stress that the author of a paper will always do well to anticipate as much as practical, any factor highly likely to be cited critically against his objectivity unreasonably, as well as reasonably. 

Again, these are GENERAL comments on my part, and not intended toward you or any other person in particular.

May progress be made, and any undeserved nitpicking or innuendo be given no more thought than appropriate to that progress.  

Avatar of:

Posts: 0

April 19, 2012

 Has anyone asked azar123 to disclose his own credentials and his own accomplishments? 

If azar123 has greater expertise to offer, what is his/her educational history.  What are some of his/her papers, that we might read them and seek to discern whether he/she has something to gain by his/her vitriolic ad hominem assertions. 

Perhaps he/she has done some work of his/her own that would, on its own merits, put to shame what you, or any other commenter here might have accomplished or presently be accomplishing.

(I've never seen students graded harder by anyone than by one associate professor who repeatedly failed to present a dissertation that passed muster.  Do you discern here what might be a whiff of sour grapes, or some such taint of emotional baggage?  What's driving this angst, do you suppose?)

Avatar of: azar123

azar123

Posts: 11

April 21, 2012

 Enough said

Science 27 January 2006: Vol. 311 no. 5760 pp. 448-449 DOI: 10.1126/science.311.5760.448a
NEWS OF THE WEEK
SCIENTIFIC MISCONDUCTFraud Upends Oral Cancer Field, Casting Doubt on Prevention TrialJennifer Couzin and Michael SchirberThe world of oral cancer research is reeling after one of its stars, Norwegian oncologist Jon Sudbø, admitted this week through his attorney to falsifying data in three seminal papers published by top medical journals. (Read more.)

Avatar of:

Posts: 0

April 21, 2012

 Enough said

Science 27 January 2006: Vol. 311 no. 5760 pp. 448-449 DOI: 10.1126/science.311.5760.448a
NEWS OF THE WEEK
SCIENTIFIC MISCONDUCTFraud Upends Oral Cancer Field, Casting Doubt on Prevention TrialJennifer Couzin and Michael SchirberThe world of oral cancer research is reeling after one of its stars, Norwegian oncologist Jon Sudbø, admitted this week through his attorney to falsifying data in three seminal papers published by top medical journals. (Read more.)

Avatar of: RonHorgan

RonHorgan

Posts: 8

April 24, 2012

Professor azar123,
                          Thank you for your cow pie recipe, I find the taste grows on me!
David Gorski's blogs on Science Based Medicine about the complexity of cancer were very enlightening.
I understand that as the cancer cells continue to divide they become more severely damaged and in effect become a cluster of diverse cells with quite different genes expressed and with the whole cell machinery looking like a a small explosion has occured.
Surely the essence of stem cells is that they are very precisely organized.
If so then direct examination of the claimed cancer stem cells should show a population of quite well organized cells within a mass of very disorganized cells?
Such a test may provide direct proof of CSC's.
Is this a practical option?

Progress from an initial injury to final malignant cancer may take up to 20-30 years.
If during all of this time the driving force behind the tumor development was cancer stem cells which have the ability to form new colonies, then why does colony formation only take place at the final stage of malignancy?

As a rhetorical answer it could be that the immune system destroys the wandering cells until late in the disease when it becomes overwhealmed?

The work mentioned earlier with the CD47 antibody  being effective at stopping cancer spread is promising.

Whatever the wandering cells are called concentration on attacking them looks like the way to go

Avatar of:

Posts: 0

April 24, 2012

Professor azar123,
                          Thank you for your cow pie recipe, I find the taste grows on me!
David Gorski's blogs on Science Based Medicine about the complexity of cancer were very enlightening.
I understand that as the cancer cells continue to divide they become more severely damaged and in effect become a cluster of diverse cells with quite different genes expressed and with the whole cell machinery looking like a a small explosion has occured.
Surely the essence of stem cells is that they are very precisely organized.
If so then direct examination of the claimed cancer stem cells should show a population of quite well organized cells within a mass of very disorganized cells?
Such a test may provide direct proof of CSC's.
Is this a practical option?

Progress from an initial injury to final malignant cancer may take up to 20-30 years.
If during all of this time the driving force behind the tumor development was cancer stem cells which have the ability to form new colonies, then why does colony formation only take place at the final stage of malignancy?

As a rhetorical answer it could be that the immune system destroys the wandering cells until late in the disease when it becomes overwhealmed?

The work mentioned earlier with the CD47 antibody  being effective at stopping cancer spread is promising.

Whatever the wandering cells are called concentration on attacking them looks like the way to go

Avatar of:

Posts: 0

April 25, 2012

All of the proponents of CSC argue ad nausea for their existence, and I wish they were right, but all, including you fail to provide a single shred of undisputed proof for their existence, what a shame.
“The work mentioned earlier with the CD47 antibody being effective at stopping cancer spread is promising.â€쳌 No it is not, it was done many times before with plural of diverse antibodies and CD47 IS NOT a CSC marker, it may over expressed on some cancer cell but has no accepted clinical utilization or diagnostic/prognostic value. Sorry.

All of the proponents of CSC argue ad nausea for their existence,
and I wish they were right, but all, including you fail to provide a single shred
of undisputed proof for their existence, what a shame.

Avatar of: azar123

azar123

Posts: 11

April 25, 2012

All of the proponents of CSC argue ad nausea for their existence, and I wish they were right, but all, including you fail to provide a single shred of undisputed proof for their existence, what a shame.
“The work mentioned earlier with the CD47 antibody being effective at stopping cancer spread is promising.â€쳌 No it is not, it was done many times before with plural of diverse antibodies and CD47 IS NOT a CSC marker, it may over expressed on some cancer cell but has no accepted clinical utilization or diagnostic/prognostic value. Sorry.

All of the proponents of CSC argue ad nausea for their existence,
and I wish they were right, but all, including you fail to provide a single shred
of undisputed proof for their existence, what a shame.

Avatar of: RonHorgan

RonHorgan

Posts: 8

April 27, 2012

Professor azar123, I am in no position to supply proof of the existence of cancer stem cells.
All that I can do is read summaries of work in this field , attempt to understand how cancer "works" and perhaps suggest simplistic ideas that may have been overlooked or ignored because of some boundary convention of which I am ignorant.
In the above post I have suggested that testing the condition of the chromosomes in the supposed cancer stem cells may be a valuable observation. If the "CSC's " have highly organized chromosomes and indeed look like stem cell and normal chromosomes, then they may indeed be CSC's.
Further if the malignant injury that they carry is not expressed  as obvious chromosome disorganization, then presumably the damage is as unexpressed genetic damage, and studying the precise nature of the damage within the "CSC's" may yield a better understanding of cancer and how to treat it.
As solid tumors develop the chromosomes become more and more disorganized until different parts of the same growth may be quite different tumors. Needle biopsy may give misleading results as the sample may be too localized.(This is my understanding from Gorskis blog)
If on the other hand the "CSC'S" do show a pattern of disorganization 
this may show that they are not true stem cells and this pattern may provide a better diagnosis of the resulting tumor.

In the next article in this magazine Lathia et al PLoS one Sept 22 2011.
is reported as having directly observed the growth of a solid brain cancer in mice from what seem to be CSC's.

Thank you for correcting me on the value of the CD47 antibody as a potential therapy. Perhaps in an immune supressed mouse introducing any antibody may retard the growth of a human exoplant?

The globular cluster of "CSC's" at the head of this article are an invitation to pluck one and examine its state of order.
Do you know if this obvious work has been done and with what results?

 

  

Avatar of:

Posts: 0

April 27, 2012

Professor azar123, I am in no position to supply proof of the existence of cancer stem cells.
All that I can do is read summaries of work in this field , attempt to understand how cancer "works" and perhaps suggest simplistic ideas that may have been overlooked or ignored because of some boundary convention of which I am ignorant.
In the above post I have suggested that testing the condition of the chromosomes in the supposed cancer stem cells may be a valuable observation. If the "CSC's " have highly organized chromosomes and indeed look like stem cell and normal chromosomes, then they may indeed be CSC's.
Further if the malignant injury that they carry is not expressed  as obvious chromosome disorganization, then presumably the damage is as unexpressed genetic damage, and studying the precise nature of the damage within the "CSC's" may yield a better understanding of cancer and how to treat it.
As solid tumors develop the chromosomes become more and more disorganized until different parts of the same growth may be quite different tumors. Needle biopsy may give misleading results as the sample may be too localized.(This is my understanding from Gorskis blog)
If on the other hand the "CSC'S" do show a pattern of disorganization 
this may show that they are not true stem cells and this pattern may provide a better diagnosis of the resulting tumor.

In the next article in this magazine Lathia et al PLoS one Sept 22 2011.
is reported as having directly observed the growth of a solid brain cancer in mice from what seem to be CSC's.

Thank you for correcting me on the value of the CD47 antibody as a potential therapy. Perhaps in an immune supressed mouse introducing any antibody may retard the growth of a human exoplant?

The globular cluster of "CSC's" at the head of this article are an invitation to pluck one and examine its state of order.
Do you know if this obvious work has been done and with what results?

 

  

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