Role of stem cells and gap junctional intercellular communication in humancarcinogenesis

Epidemiological data, experimental animal bioassays, studies of in vitro ne oplastic transformation, and molecular oncology studies have implicated a m ultistage, multimechanism process in human carcinogenesis. From animal carc inogenesis studies, the operational concept of a single normal cell being i rreversibly altered during the first step in carcinogenesis is called initi ation. The subsequent interruptible or reversible clonal expansion of these initiated cells by non-cytotoxic mitogenic stimuli, compensatory hyperplas ia due to cell death by necrosis, or inhibition of apoptosis is referred to as the promotion phase. Last, when one of these clonally expanded, initiat ed cells acquires sufficient genetic/epigenetic alterations to become neopl astically transformed and acquire the phenotypes of promoter independence, invasiveness and metastasis, it is referred to as the progression step of c arcinogenesis. This report hypothesizes that the single normal cell that is initiated is a pluripotent stem cell. By assuming that the normal pluripot ent stem cell is immortal and becomes mortal when induced to terminally dif ferentiate, initiation would be viewed as the irreversible process by which a stable alteration in a finite number of proto-oncogenes and/or tumor sup pressor genes could block terminal differentiation or "mortalization", Prom otion would involve the reversible inhibition of gap junctional intercellul ar communication (GJIC) and while progression occurs with the stable down-r egulation of GJIC. (C) 2001 by Radiation Research Society.