Decline and fall of the tumor suppressor

Epidemiological studies show that cancer is primarily a disease of the aged. Cancer rates increase dramatically in humans beginning in the six and seventh decades of life (1). Although the complex relationship between cancer and aging has long been recognized, a clear understanding of the mechanisms behind this relationship has remained elusive. Among the genes that protect us from early cancers are the tumor-suppressor genes, a category of genes that generally encode negative growth regulators. Yet the frequent cancers in older individuals suggest that the tumor-suppressor genes somehow lose their effectiveness late in life. Are the tumor suppressors in aged individuals actively promoting cancers, are they losing their cancer-prevention function, or are they at the mercy of larger forces that circumvent or eliminate their function? In a recent issue of PNAS, the article by Feng et al. (2) provides compelling evidence that some tumor suppressors remain structurally intact but decline in functional activities during aging.

So why do tumor suppressors become less effective in preventing cancer with age? One dominant theory is that cellular mutation loads increase with age in tissues (3). It has been proposed that the emergence of a cancer cell may be the result of an unlucky accumulation of mutations in a set of cooperating oncogenes and tumor-suppressor genes (4). This proposal suggests that innate tumor-suppressor function does not have to change but its function can be eliminated as a result of mutagenic insults. However, Feng et al. (2) add a new twist by showing that cancers in the aged are not merely the result of accumulated oncogenic mutations but may be partially dependent on intrinsic nonmutational declines in tumor-suppressor function.

The tumor suppressor in question is p53, also known as the “guardian of the genome,” which responds to an array of cellular stresses and mediates cell …

*To whom correspondence should be addressed. E-mail: larryd{at}bcm.tmc.edu