Genetic, epigenetic, dysgenetic and non-genetic mechanisms in tumorigenesis. II. Further delineation of the rate limiting step.

A not yet understood phenomenon in carcinogenesis is presented by the enormous species-specific and age-specific differences in cellular susceptibility to malignant transformation. Murine cells are 100,000 times fold more susceptible than human cells. A previous review article suggested the promotion phase as the key for this difference. Presently, a further analysis of literature data indicates that promotion results in the dedifferentiation of cells, which, in initiated cells, leads to an imbalanced regenerative growth of stem-cell-like cells. As aging results in the loss of adaptive functions and in a decreased response to growth stimuli, dedifferentiation of old cells is supposed to increase the imbalance of the regenerative growth for initiated cells and consequently to enhance the chance for immortalization of these cells. As immortalization is accompanied by chromosomal dysgenetics, malignant conversion by the appearance of secondary genetic events during multistage carcinogenesis is not just a matter of random chance for additional mutations, but is determined to some degree by the condition of the initiated target cell and to the species to which the target cell belongs.