Cellular aging and cancer

Abstract

Aging is manifest in a variety of changes over time, including changes at the cellular level. Cellular aging acts primarily as a tumor suppressor mechanism, but also may enhance cancer development under certain circumstances. One important process of cellular aging is oncogene-induced senescence, which acts as a significant anti-cancer mechanism. Cellular senescence resulting from damage caused by activated oncogenes prevents the growth of potentially neoplastic cells. Moreover, cells that have entered senescence appear to be targets for elimination by the innate immune system. In another aspect of cellular aging, the absence of telomerase activity in normal tissues results in such cells lacking a telomere maintenance mechanism. One consequence is that in aging there is an increase in cells with shortened telomeres. In the presence of active oncogenes that cause expansion of a neoplastic clone, shortening of telomeres, leading to telomere dysfunction, prevents the indefinite expansion of the clone, because the cells enter crisis. Crisis results from chromosome fusions and other defects caused by dysfunctional telomeres and is a terminal state of the neoplastic clone. In this way the absence of telomerase in human cells, while one cause of cellular aging, also acts as an anti-cancer mechanism.

Figure 1

Simplified model for the cooperation of activated Ras and SV40 T antigen used in the authors’ experiments described in the text. Constitutively activated (mutated) Ras has a broad variety of downstream molecular targets and effects on cell behavior. Some of those are indicated in the box on the right (increased cell proliferation, lowered dependence on external mitogens, loss of dependence on anchorage for growth; in vivo, Ras promotes invasiveness and tumor formation, e.g. in immunodeficient animals). However, at levels of expression that exert these effects, the hyper-replication caused by Ras results in senescence via mechanisms discussed in the text. Senescence occurs via the activation of the p53 and Rb pathways. SV40 TAg acts to overcome senescence by interrupting these pathways, thereby permitting the expression of the full spectrum of pro-tumorigenic effects of Ras, although it also probably directly contributes to some of those properties. See text (Sections 2.3 and 3.1) for futher details.