Tumorigenesis: The Adaptation of Mammalian Cells to Sustained Stress Environment by Epigenetic Alterations and Succeeding Matched Mutations
Recent studies indicate that during tumorigenic transformations, cells may generate mutations by themselves as a result of error-prone cell division with participation of error-prone polymerases and aberrant mitosis. These mechanisms may be activated in cells by continuing proliferative and survival signaling in a sustained stress environment (SSE). The paper hypothesizes that long-term exposure to this signaling epigenetically reprograms the genome of some cells and, in addition, leads to their senescence. The epigenetic reprogramming results in: (i) hypermethylation of tumor-suppressor genes involved in the onset of cell-cycle arrest, apoptosis and DNA repair; (ii) hypomethylation of proto-oncogenes associated with persistent proliferative activity; and (iii) the global demethylation of the genome and activation of DNA repeats. These epigenetic changes in the proliferating cells associate with their replicative senescence and allow the reprogrammed senescent cells to overcome the cell-cycle arrest and to activate error-prone replications. It is hypothesized that the generation of mutations in the error-prone replications of the epigenetically reprogrammed cells is not random. The mutations match epigenetic alterations in the cellular genome, namely gain of function mutations in the case of hypomethylation and loss of functions in the case of hypermethylation. In addition, continuing proliferation of the cells imposed by signaling in SSE speeds up the natural selection of the mutant cells favoring the survival of the cells with mutations that are beneficial in the environment. In this way, a stress-induced replication of the cells epigenetically reprograms their genome for quick adaptation to stressful environments providing an increased rate of mutations, epigenetic tags to beneficial mutations and quick selection process. In combination, these processes drive the origin of the transformed mammalian cells, cancer development and progression. Support from genomic, biochemical and medical studies for the proposed hypothesis, and its implementations are discussed.
Karpinets, T. V.,
& Foy, B.
(2005). Tumorigenesis: The Adaptation of Mammalian Cells to Sustained Stress Environment by Epigenetic Alterations and Succeeding Matched Mutations. Carcinogenesis, 26 (8), 1323-1334.