Devil’s bargain: Tradeoffs between stem cell maintenance and tumor suppression

An emerging theme in biogerontology is the idea that lifespan may be determined by the balance between regeneration and tumor suppression. Long-term tissue health demands that damaged and dead cells be replaced, but unlimited replicative potential poses the risk of cancer. Therefore, to prevent tumors, organisms must accept a decrease in regenerative capacity.

A recent review addresses the relationship between tumor suppressor gene activity and the ability of the stem cell compartment to regenerate. Gatza et al. discuss the evidence that p53 gene dosage is inversely correlated with a number of metrics of stem cell performance:

The ability of tissues to maintain homeostasis is dependent in part on the function of adult tissue stem cells, which have the capability to self-renew and differentiate into multiple lineages. It has been hypothesized that the ability of stem cells to maintain tissue homeostasis declines functionally with age and that this decline may account for many of the biological phenotypes associated with aging. … Our recent findings suggest that p53 may impact hematopoietic stem cell (HSC) dynamics during mammalian aging. … [W]e have shown that alteration of p53 activity affects stem cell number, proliferation, and functionality with age. Several other recent studies have implicated other tumor suppressors in potential age-related regulation of HSC dynamics as well. These data support a model in which aging is caused in part by a decline in tissue stem cell regenerative function, regulated in part by tumor suppressors.

How direct is this connection? In an indirect model, differentiated cells are the initiatiors of tumor growth. p53 limits stem cell proliferation, which in turn decreases the rate of production of new differentiated cells. Fewer cells available to undergo neoplastic transformation means fewer cells available to initiate tumors, with the unfortunate consequence that tissues requiring new cells to maintain homeostasis must go begging.

In a direct model, tumor suppressor activity decreases the number of stem cells that might become dysregulated and transformed into cancer stem cells, a relatively new concept in cancer biology. The New York Times provides an excellent lay introduction to the subject:

One day, perhaps in the distant future, stem cells may help repair diseased tissues. But there is a far more pressing reason to study them: stem cells are the source of at least some, and perhaps all, cancers.

At the heart of every tumor, some researchers believe, lie a handful of aberrant stem cells that maintain the malignant tissue.

The idea, if right, could explain why tumors often regenerate even after being almost destroyed by anticancer drugs. It also points to a different strategy for developing anticancer drugs, suggesting they should be selected for lethality to cancer stem cells and not, as at present, for their ability to kill just any cells and shrink tumors.

Regardless of where in the differentation process once believes cancer is originating, either model presents a quandary for the therapeutic use of stem cells and the optimization of lifespan. Too much of a good thing — in this case, regenerative capacity — can kill you.

Related articles: We’ve discussed the evolutionary tradeoff between cancer and regeneration before, in the context of another tumors suppressor called p16. The relevant articles:

• p16 vs p16: Preventing cancer, limiting self-renewal
• p16 in the pancreas
• Pancreatic proliferative potential: Protracted posting
• p16 and neural progenitors in the brain
• p16, senescence, and kidney transplantation