Apoptosis: Inhibitor or Instigator of Carcinogenesis?

Abstract

Carcinogenesis is considered to require an initiating event that results in an irreversible genetic change in a subpopulation of cells. Based on the available evidence, it seems likely that apoptosis may act to attenuate this process by causing the deletion of genetically damaged cells from the host organism. Nevertheless, the existence of an active pathway leading to apoptotic cell death may be a double-edged sword, simply because it can be overcome. Some cells may exhibit preexisting genetic or epigenetic insensitivity to induction of apoptosis. Surviving cells may contain sub- lethal levels of DNA damage and be induced to proliferate as an indirect result of the carcinogen-induced apoptotic cell death of surrounding tissue. This process would facilitate the acquisition mutations in the genome, possibly resulting in further insensitivity to apoptosis through activation of the bcl-2 oncogene or inactivation of the p53 tumor suppressor gene. In this context, the propensity of a cell to undergo apoptosis could be viewed as a selection pressure that a tumor cell must overcome. For neoplastic growth to occur, an imbalance between proliferation and apoptosis must be established such that cell growth predominates. Genetic mutations or epigenetic factors that diminish the propensity of a cell to undergo apoptosis may therefore confer on that cell a growth advantage.