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Published online 3 December 2008 | Nature 456, 553 (2008) | doi:10.1038/456553a
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Melanoma in mice casts doubt on scarcity of cancer stem cells
Tumour treatments may need a rethink.
The rare 'cancer stem cells' thought to seed cancer growth are not so rare after all, according to researchers in Michigan. If they're right, then the strategies used for some cancer therapies may need to change.
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Just out of curious ... when consider together with the fact that stem cells can be regenerated from differentiated cells by humans through turning on or off certain signaling molecules, why can a tumor cell turn itself into either a cancer stem cell or not by accumulated mutations during the transformation processes? How about a hypothesis that every cell can be turned into cancer stem cell ... it simply depends on the mutations one cell got during the transformation processes. Then, the frequency of finding cancer stem cells could be the result of mutations the "experimental cancer cells" got. If tumor heterozygosity can be developed during the transformation processes and tumor genotype can determine their malignancy, both observations could support this hypothesis. If this is the case, one cell after couple generations might be able to generate different "cancer stem cell recovery frequency" based on the mutations the offspring cell got. Thoughts?
The paper by Quintana et al, demonstrates that under favorable xenotransplantation conditions, the frequency of tumorigenic cells in human melanomas is surprisingly high. The paper is accompanied by appropriate caveats against overgeneralization, but still requires us to reconsider some of our perspectives on the putative rarity of "cancer stem cells". These indeed appear to be rare in many hematopoietic malignancies, but perhaps less rare in other tumor types. In the case of solid tumors, one must consider a spectrum of possibilities. The authors did not detail the histopathologic nature of the melanomas they studied, but it is frequent to find many squamous cell carcinomas, for example, that exhibit a mixture of cell types within an individual tumor - ranging from those that appear undifferentiated to those (often a majority) that have progressed to differentiated or even cornified phenotypes unlikely to be capable of replication. Self-renewing cells in these tumors are likely to be much rarer than in tumors with a less differentiated morphology, where many cells might retain self renewal properties. It's also important, however, to view "stemness" as itself a spectrum rather than a narrowly defined property. Even normal stem cells can be shown to exhaust their self renewal potential over a sufficient number of generations (particularly under proliferative stress), and it is likely that cancer cells may possess "self renewal up to a limit", with the limiting number of generations differing from one cell or one cancer to another. In this regard, it's important not to interpret the formation of a palpable tumor in mice as necessarily signifying unlimited renewal potential. The authors recognize this consideration, and acknowledge that their results do not necessarily show which cells, or how many, contribute to tumor progression in humans.
I was very intrigued by the Quintana et al paper showing that tumor initiating cells were common in melanomas.This demonstration was dependent on a more permissive host but also on suspending the tumor cells in Matrigel. The Pretlows were the first to show very enhanced tumor takes when transplanting prostate cancer cells in Matrigel. Many others have had similar findings with a variety of tumor types. Interestingly, Fridman et al Int J Cancer 51;740 1992 showed that NIH3T3 cells would also form tumors when implanted in mice in Matrigel. There is likely to be an unexpected role for components of Matrigel in the phenomena described by Quintana et al. George Martin