Validity of the cancer stem cell concept under discussion

by Alexey Bersenev on December 28, 2008 · 4 comments

in cancer stem cell, under discussion

Everything we’ve learned about cancer can be summarized as ‘unpredictable and wildly varying’. To go into a tumour and think that if there’s a cancer that marker will always be there, I think that’s naive.

(Glenn Merlino – National Cancer Institute)

Actually, the discussion about the existence and significance of the so-called “cancer stem cell” (CSC) has been going on since the concept was proposed. But now, after recent findings, it’s become especially hot.

Today I’d like to bring to your attention a lot of citations from the experts in the field – scientists and clinicians, which could help us to figure out what’s going on right now, and highlight the current status of the concept and challenges. Significant parts of these citations are taken from a recent posts on the Niche blog – Cancer stem cells: controversies and misconceptions and Nature Reports Stem Cells story – Cancer stem cells, becoming common.

I’d start from citations of Sean Morrison, whose work accelerates discussion:

We’re suggesting that the cancer stem cell model will be true in some cancers and not in others.

If you really want to understand cancer, you need to take time to improve the assay, rather than taking a one-size-fits all approach.

No paper in the entire field of cancer stem cell biology has been able to determine which cells are actually fated to contribute to disease progression in the patient.

The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells.

There are some people out there who look at the paper and say that this completely invalidates the cancer stem-cell field. That’s an over-interpretation

William Kaelin (Dana-Farber Cancer Institute, Harvard Medical School, Boston):

If it turns out that the cells were never rare, then we’ve been studying those cells all along. And a cancer stem cell is just a cancer cell.

What the Morrison result says is that if you change the strain of the mouse and you do some simple tricks, you get a very different answer, at least in terms of the frequency of the cell, raising the question of what you were measuring in the first place.

Michael Clarke (Stanford University):
He identify for the first time CSC in human solid tumors.

We’ve looked at 40-odd colon cancer tumours, 20 head and neck tumours, 20 breast tumours, and I can tell you the frequency of the stem-cell population by phenotype varies from a low of about 0.6% to 45 or 50%, and the average is probably 5 or 10%.

Peter Dirks (Hospital for Sick Children, Toronto, Ontario):
He identify for the first time CSC in human glioblastoma.

Rarity isn’t necessarily a defining property of a cancer stem cell.

Andreas Strasser (Walter and Eliza Hall Institute of Medical Research, Melbourne):

He one of first called into question the rarity of cancer stem cells. He showed that when murine leukemic cells were transplanted into murine recipients frequency of cancer-initiating cells was very high (~1 in 3).

About difference between “cell of origin” and CSC:

To name these two cells with the same name is absolutely insane; until we clean that up, there will not be any progress because people don’t know what they are talking about

About “little use in chasing special subsets”:

Most notably, in human acute myeloid leukemia, only a minute proportion of the cells, displaying a defined phenotype, could seed leukemia in mice. Xenotransplantation, however, may fail to reveal many tumor growth–sustaining cells because the foreign microenvironment precludes essential interactions with support cells. In studies that instead have transplanted mouse leukemias and lymphomas into syngeneic animals, most of the tumors seem to be maintained by the dominant cell population, and only a few types of mouse leukemia seem to be sustained by a minor tumor growth–sustaining subpopulation.

John Dick (University of Toronto, Ontario Institute for Cancer Research):
His group identify for the first time human CSC from leukemic patients and one of creators of the concept.

However, some have gone a step further, taking results such as those of the Quintana report to indicate that the seeming existence of CSCs in human cancer is simply an artefact of the experimental system. One must be careful, however, not to generalize results from one tumor type (in this case, melanoma) to all forms of cancer. Furthermore, arguments against the existence of CSCs are commonly rooted in misconceptions regarding the core tenets of the model, and often raise issues with concepts that are not central to the CSC hypothesis.

In fact, the CSC hypothesis was originally proposed as an alternative to the stochastic model to explain the observed functional heterogeneity within tumors, and does not make any predictions as to frequency. Indeed, it is becoming clear that the frequency of cells with cancer-initiating ability varies significantly with tumor type (for example, they appear to be more frequent in lymphoid versus myeloid hematologic malignancies.

Overall, these results demonstrate the inherent variability of tumor biology, and indicate that the CSC model should not be considered universal, either in mice or humans.

As a final point, we would like to re-iterate the distinction between the concepts of CSCs (cells within a tumor that possess stem-like properties) and “cell of origin” (the normal cell type in which the tumorigenic process is initiated, whether a stem cell or progenitor). The CSC model does not make any assumptions regarding the origins of CSCs – indeed, there is now abundant evidence that CSCs in mice may arise from either normal stem or progenitor cells depending on the specific transforming events, although evidence in human cancers is still lacking.

Scott Kern (John Hopkins Medical School):

Cancer stem cells are hard to identify because a practical operating definition has never been achieved. Even if 100% of cells in a tumour could re-initiate a tumour, inefficiencies of the assay would make the number identified less than 100%

David Taussig (St. Bartholomew’s Hospital, UK):
His recent report raised questions regarding the validity of experiments using antibodies to fractionate tumor cells before xenotransplantation assay.

The cancer stem cell hypothesis does not say that all cancer stem cells are derived from normal stem cells.

Fourth, both commentators indicate that our data are against the cancer stem cell hypothesis, and yet the effects of anti-CD38 antibody were also seen on normal haematopoietic tissue. Does this mean that normal haematopoietic stem cells do not exist either? We interpret our data to indicate that the phenotype of leukaemic stem cells is more heterogeneous than the original publication suggested. This is entirely consistent with the genetic and clinical heterogeneity of AML.

Craig Jordan (University of Rochester):

Whatever we’re defining as a cancer stem cell is not very stable, so the frequency and phenotype may be changing.

If you think about metastasis — a single cell going from a primary tumour to a distant site and re-creating a complex tumour — that by definition is a cancer stem cell.

Robert Weinberg (MIT, Boston):

Cells within a tumour are not irrevocably in stem-cell and non-stem cell states.

The more we study cancer stem cells, the more we find that they are very similar to normal stem cells.

William Matsui (Johns Hopkins University):

The cancer stem cell concept — maybe its greatest utility is just a better perspective to look at the cancers. You have stem cell haters and stem cell lovers, and both groups are just entirely too dogmatic.

Connie Eaves (Terry Fox Laboratory, University of British Columbia):

Research into human cancer stem cells is still gathering steam, so it is not clear how unusual or clinically relevant Quintana and colleagues’ observations are. It is possible that their findings are unique to a subset of tumours, to specific types of mutation, to certain states of cancer progression, to distinct factors within the tumour environment, and/or to the states of innate and acquired immunity of the host. Equally possible is that these observations are more commonly applicable. Either way, this study provokes healthy scepticism in the absolute value of any tumour-initiating cell measurement and points to the need for careful studies designed to test new biomarkers and therapeutics.

Joseph Lipsick (Stanford University):

It has been known for decades that cancer cells have stem cell–like properties of self-renewal (the artist formerly known as ‘immortality’). The initial formulation of the cancer stem cell hypothesis therefore held that most cancers must arise from normal stem cells. This is clearly not the case in a variety of human cancers and animal models. It now appears likely that the remainder of the cancer stem cell hypothesis may also fall by the wayside.

In an era of limited resources for biomedical research, one therefore wonders how much time, effort and money should continue to be spent in this area.

I’d like to finish by citation of Jenny Chang (Baylor College of Medicine):

The purist may not buy that, but in the clinical setting, the only importance is ‘what are the characteristics of the resistant population that appear to be able to make new cancers?

You are very welcome to comment!
picture credit: the Economist

{ 2 comments… read them below or add one }

Alex January 5, 2009 at 12:43 pm

I got a reply to this discussion via email from Dr. R. Rajaraman. He agreed to posted it here:

It is well known that from the beginning,this hypothesis was haunted by the possible detrimental effects on cells during isolation and sorting cells for xeno-transplantation studies. In addition the studies by Taussig et al has demonstrated that even in hAML system, which need not use drastic enzymatic digestion to isolate single cells, the simple process of exposing the cells to antibodies will drastically affect the viability of cells in the NOD/SCID mice system. This has been born out by the studies of Quintana et al. Besides, nobody knows about the source of the putative cancer stem cells. In addition, there is not direct proof for the asymmetric division potential of the so called CSCs.
What worries me is the act that there are much better explanations for the process of carcinogenesis. For example, my work on neosis, which nobody seems to care about has offered a perfectly logical explanation for the origin of tumor initiating Raju cells, which are produced repetitively. This will explain the variation in the number of tumor initiating cells. In addition, we have shown that when tumor cells are exposed to current non-surgical treatments, the cells enter senescent phase and undergo neosis which yields Tumor Repopulating Raju cells which are resistant, thus giving rise to the resistant tumor growth. (Ref: R. Rajaraman et al. Cancer Cell Int 2006.6:25) Complete info can be seen in the internet by googling for the words “Neosis + R. Rajaraman”. I would personally welcome your comments on this hypothesis, which is based on video documentation, unlike the CSC hypothesis, which is based on assumptions and circumstantial evidence, which has now turned out to be erroneous.

please welcome to comment!


Dr. R. Rajaraman July 12, 2010 at 7:29 pm

There is new evidence for the concept of neosis executes Epithelial-Mesenchymal Transition. In addition, the so called Cancer Stem Cells are only short-lived and these cells soon undergo Mesenchymal-epithelial transition. This fits very well with the neosis paradigm of carcinogenesis, which states that Tumor Initiating or Repopulating Raju Cells (TIRCs or TRRCs) are produced repeatedly during the continuous growth of tumor cells. Just as in the case of embryonic development, where cells undergo several EMTs and METs, tumor cells also undergo several EMTs and METs during their growth, each time producing newer batches of Tumor Repopulating Raju cells either spontaneously or after genotixin-therapy-induced senescent phase, that results in the growth of resistant cells, via EMT followed by neosis. Thus Raju cells represent the progenitor cells, that undergo transit amplification to mature into cancer cells and do not fit to be called cancer stem cells. This signifies the importance of neosis playing a dynamic role in tumor growth and origin of tumor cell heterogeneity. Dr. Denys Wheatley, Edior in Chief of BioMed Central, has written four editorials in support of neosis and has warned that Cancer biologists, Cell biologists, Pathologists and Clinician scientists ignore neosis “to their own peril”.


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