28 January 2013
It is widely accepted (appreciated?) that tumors are tantalizingly heterogeneous; they are not just a ball of cancer cells. A proverbial mountain of research has emerged characterizing most solid tumors as a hierarchy of different cell types that contribute to what might be best viewed as a pseudo-organ with its own perverse “homeostasis.” There has emerged the model of the “Cancer Stem Cell” (CSC) in which a small population of tumor cells can give rise to an entire (heterogeneous) tumor.
The CSC model is attractive for several reasons:
1) It provides a model of carcinogenesis in which the long-lived stem cells in tissues are the ones that acquire mutations and go awry; already containing some of the hallmarks of cancer (self-renewal, resistance to apoptosis)
2) It provides a mechanism for how tumors can become heterogeneous, as stem cells are capable of giving rise to more than one cell type.
3) It would explain how tumors become resistant to chemotherapy, and suggests a means fight target tumors with much less side-effects!
I will not delve into reason #1 here, but reason #3 is of great personal interest (I admit I’m a sucker for things that could greatly improve cancer therapy). The approach is this: target the CSC’s so the tumor cannot renew itself! (illustrated above, courtesy: wiki commons)
However, a recent phenomenon reported by Robert Weinberg’s group suggests that this process is not unidirectional, and that a small population of non-CSC’s can convert back to CSC’s. At his talk last week, Weinberg presented even more compelling data than was shown in the PNAS paper.
Confusing? You bet. (I would show the actual data in the paper, but I’m pretty sure I’d be violating copyright laws for that one) Apparently, one would need to design drugs to both kill CSC’s, and prevent the spontaneous de-differentiation into CSC’s…
At this point, I’m left wondering about the entire “Cancer Stem Cell” or “Cancer Progenitor Cell” label. It could be that ALL tumor cells are capable of reverting back to CSC’s. Weinberg assumes this is not so in follow-up reviews in the literature, and proposes a third population of “non-CSC” or “dormant-CSC” with little evidence to suggest that such a population exists.
Unidirectional differentiation is central to the CSC model, and how we would use the theory to design therapeutic approaches. Perhaps it’s time to take a step back and re-draw the model from scratch in light of the new data? This is something I’ll spend more time thinking about myself.
I wish I could end this post with a concise story and model. Unfortunately, I only have ambiguity of rapidly changing models of cancer metastasis for the time being. I’m willing to bet other research groups are working on this as I type this, and I will re-visit this topic in the future as more research comes to light.