Model of the developing tumorigenic phenotype in mammalian cells and the roles of sustained stress and replicative senescence.
The molecular mechanisms that drive mammalian cells to the development of cancer are the subject of intense biochemical, genetic and medical studies. But for the present, there is no comprehensive model that might serve as a general framework for the interpretation of experimental data. This paper is an attempt to create a conceptual model of the mechanism of the developing tumorigenic phenotype in mammalian cells, defined as having high genomic instability and proliferative activity. The basic statement in the model is that mutations acquired by tumor cells are not caused directly by external DNA damaging agents, but instead are produced by the cell itself as an output of a Mutator Response similar to the bacterial "SOS response" and characterized by the initiation of error-prone cell cycle progression and an elevated rate of mutation. This response may be induced in arrested mammalian cells by intracellular and extracellular proliferative signals combined with blocked apoptosis. The mutant cells originated by this response are subjected to natural selection via apoptosis and turnover. This selection process favors the survival of cells with high proliferative activity and the suppression of apoptosis resulting in the long run in the appearance of immortalized cells with high proliferative activity. Either a sustained stressful environment accompanied by continuing apoptotic cell death, or replicative senescence, provides conditions suitable for activation of the Mutator Response, namely the emergence of arrested cells with blocked apoptosis and the induction of proliferative signal. It also accelerates the selection process by providing continuing cell turnover. The proposed mechanism is described at the level of involved metabolic pathways and proteins and substantiated by the related experimental data available in the literature.
Karpinets
Tatiana V
TV
Department of Physics, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA. tatiana.karpinets@wright.edu
Foy
Brent D
BD
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002477:Cells / Q000473:pathology*; D016922:Cellular Senescence; D042822:Genomic Instability; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D013312:Stress, Physiological