Posted by: Dan | January 9, 2007

Revisiting the Stem Cell Theory of Cancer

Jake on Pure Pedantry has an interesting post on Evidence for the stem cell theory of cancer development, which I’ve commented on before. Jake’s post is based on a Nature Genetics paper by Martin Widschwendter et al.

I still don’t buy the stem cell theory of cancer. Without a doubt though, some pluripotent cells undergo clonal expansion into neoplastic lesions, and cancer cells share a variety of regulatory characteristics with stem cells. But I think it’s much more accurate to say that cancer cells utilize whatever there is available to get around the roadblocks to proliferation and clonal expansion. Stem cells carry some of these characteristics, and so it makes sense that cancer cells would co-opt the molecular tools which facilitate such characteristics.

Thus, the conclusion that stem cells are the source of neoplasms – though perhaps true some of the time – is incomplete. It’s not a comprehensive description of cancer progression, and does not supplant the other various causes of cancer, including chemical and viral. For later stages, it does not reconcile the roles of chromosomal damage, elevated tyrosine kinase signaling, or why p53 and other vital tumor suppressors may be lost, in many cancers.

But most critically in this topic, Widschwendter and colleagues base their support of this theory on the correlation of a set of epigenetic markers, not a cause and effect study. They simply do not address whether tumor cells could have acquired the DNA methylation signature that they examine without originating from stem cells, which I think is still a perfectly reasonable possibility.

Methinks the evidence for this theory is still fleeting.


Responses

  1. […] previously mentioned that I’m rather skeptical on the stem cell theory of cancer, even if it may be clear that […]

  2. To me this is all semantics. Cancer stem cells, cancer sustaining cells, cancer propagating cells. It is of no relevance to those who anti-cancer therapy is failing if the cells which are killing them are truly derived from somatic stem cells or not. Ask Leroy Sievers if he cares. Fact of the matter is that most currently available anti-cancer drugs, targeted or not, fail to eradicate tumours because there appears to be a subpopulation of cells which is resistant and this resistance is believed to exist a priori by those who know a lot more about this than myself (I am just back from the 10th Beatson International Cancer Conference in Glasgow, Scotland, where this issue was discussed). If we want to beat cancer, we will have to get at these cells. We will have to isolate them, study them, and find drugs which kill them without killing the patient. Rudolf Virchow was one of the early proponents of the cancer stem cell theory. He seems to have been right about the link between inflammation and cancer. My gut feeling is that he has been right about cancer stem cells, as well. But the jury is still out (see article by Kelly et al. in today’s Science).

  3. I of course agree with most of that, although I think I word things a bit differently. My concern is the over-use of the label “the cancer stem cell theory of cancer,” which implies that that is the sole cause of cancer. You’re right, it’s not – but it is linked to cancer as one such factor that facilitates the first stage(s) of cancer. The same is true of aneuploidy, inflammation, and random mutation. They all contribute.

    The bogus part is “Ask Leroy Sievers if he cares” – it’s irrelevant whether a patient cares, he doesn’t have to understand whats happening in his body to know and fear his own end. His doctors damn well should care however – keeping up to date on our understanding of how cancer works will help them help him better.

  4. Clearly there is compelling evidence that a side population of highly tumorigenic cancer cells being in the minority group at least in primary tumours, exists.

    It has been established that these cells are largely impervious to current treatment regimens.

    I find it rather intriguing that these so called cancer stem cells, have also been detected circulating in bone marrow samples from patients diagnosed with very early breast cancer. Even more interesting is the observation, that in these micrometastatic deposits, the cancer stem cells comprised the majority of circulating tumour cells ( up to 70%). A lot of cells waiting to seed metastases perhaps?

    Whatever we think of cancer, it must be recognised that tumours are mutated forms of tissue development. It is generally believed that tissue is largely dependant on stem cells for regeneration and repair. Why would cancerous tissue be any different in that regard?

    Scientists can spend another 30 years trying to determine the biological basis of cancer and that is a worthy goal to be sure, but nothing says that we should not be spending time targeting these cells in the meantime.

    Several decades of chemotherapy radiotherapy, hormone therapy, and so on have failed to yield real and consistent cures in metastatic cancer.

    Its time to target these particular cells that I believe are the real culprits behind metastatic disease. Lets convert a fatal condition into a chronically manageable one. Then when science finally understands the molecular workings of cancer we might be able to eradicate the disease entirely.

  5. Dear Dan and Chris!

    I mentioned Leroy Sievers because what riles me is that a
    lot of the debate around cancer stem cells is rather academic, preventing the issues most relevant to doctors and patients from being addressed. I speak from experience.

    (As an aside: a critical appraisal of modern biomedical research can be found here:

    Modern biomedical research: an internally self-consistent universe with little contact with medical reality? by D.F. Horrobin in Nature Reviews Drug Discovery 2, 151-154.)

    For those trying to find treatments for cancer, it is irrelevant if tumour cells carrying stem cell markers are derived from somatic stem cells or even if they are the only ones which can initiate and sustain a tumour. What matters is if these cells are the cause of ultimate treatment failure because they are intrinsically resistant to everything we can currently throw at tumours. There has been a lot of talk ever since the War on Cancer was declared about making cancer a manageable, chronic condition. There has been to little progress towards this goal, in my humble opinion.

    Burkhard

  6. […] commented on the stem cell theory of cancer previously, including some of its strengths and weaknesses. And as Marx notes, it is indeed this […]


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