Cellular Senescence And Cancer

Much of the evidence that links cellular senescence and tumor suppression derives from studies of cells in culture. Nonetheless, there is substantial supporting evidence from studies of intact organisms. Perhaps the best evidence derives from mice in which genes encoding p53 or INK4a proteins have been inactivated in the germ line. The INK4a locus encodes the p16 CDKI, as well as p14/ARF, a protein that is derived from an alternative reading frame and indirectly regulates p53 stability (145,146,153). Cells derived from animals that lack a functional INK4a locus fail to senesce in response to multiple stimuli. In all cases, the animals develop cancer at an early age (154). Similarly, p53 -/- mice are composed of cells that re sist or fail to respond to senescence signals, and these animals are highly cancer prone (155-157). By contrast, a genetic manipulation that causes mammary epithelial cells to undergo premature replicative senescence suppresses the development of breast cancer in young mice exposed to the mouse mammary tumor virus (158). Human cells are markedly more resistant to neoplastic transformation than mouse cells. Nonetheless, in humans and mice, mutations that disrupt the senescence response generally lead to increased cancer incidence. One example is cells from humans with the Li-Fraumeni syndrome, a hereditary cancer-prone syndrome caused by mutations in p53 (159,160). These cells immortalize at a frequency that is well above the vanishingly low immortalization frequency of normal fibroblasts (161). Thus, there is increasing evidence that cellular senescence constitutes an important defense against the development of cancer in mammals, including humans.

Hanahan and Weinberg have proposed that cells must acquire a defined number of traits for a malignant tumor to form: unregulated growth (hypersensi-tivity to positive signals, resistance to inhibitory signals), resistance to apoptosis, unlimited replicative potential, angiogenesis, invasion, and metastasis (9). Clearly, a large number of mutations are required for cells to acquire these traits. It is not surprising, then, that most cancers show signs of genomic instability, which accelerates the acquisition of oncogenic mutations (4,5,162) (see Fig. 1). The most important function of cellular senescence may be to prevent the growth of cells at risk for developing chromosomal instability. Perhaps the greatest risks to genomic stability are telomere dysfunction and direct DNA damage, particularly DSBs (3,163-165). Both, of course, are potent inducers of the senescence response (19,24,47,166-168).

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