How carcinogens (or telomere dysfunction) induce genetic instability: associated-selection model.
Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair per se provide an immediate growth advantage. According to the 'associated-selection' model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The 'associated-selection' model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed.
Blagosklonny
M V
MV
Medicine Branch, National Cancer Institute, NIH, Bldg. 10, R 12 N 226, Bethesda, MD 20892, USA. mikhailb@box-m.nih.gov
D002273:Carcinogens / Q000494:pharmacology*; D004260:DNA Repair; D008954:Models, Biological; D016615:Telomere
D002273:Carcinogens