IMMORTALIZATION OF SYRIAN-HAMSTER EMBRYO CELLS - PROBABILISTIC EVENT OR DETERMINISTIC PROCESS

Previous findings on the induction of immortalization in SHE cells hav e been explained with the activation/alteration hypothesis which postu lates that treatment with a carcinogen results in the induction of a s o-called ''activated state'' which enhances the rate of a probabilisti c event in the progeny of the treated cells. This event is supposed to be a mutation. Because it has been recently indicated that in mammali an cells the switching on of signal transduction pathways by 12-O-tetr adecanoyl-phorbol-13-acetate (TPA) or carcinogens can lead to genetic instability in the progeny of the treated cells, the possibility of an analogy between the induction of genetic instability and induction of immortalization after treatment with TPA was investigated. No effect of TPA was found on the rate of immortalization/cell/generation, not i n otherwise untreated cells nor in cells treated with benzo(a)pyrene. TPA was found to enhance the life span of SHE cells. The life span of a culture correlated with its growth rate and its cell density at conf luence both in the absence and presence of TPA. These correlations are supposed to reflect a regulation mechanism involved in the program of cellular senescence, and supposedly TPA can partly reverse this progr am. Treatment with benzo(a)pyrene also interferes with the life span r esulting in premature senescence in most of the cells and extension of life span in a small fraction of the cells which subsequently can bec ome immortal. Repeated switching from logarithmic growth to G0 also en hanced life span and rate of immortalization. The findings indicate th at the activated state is a disturbance of a differentiation program a ffecting in SHE cells the program of cellular senescence and that, as an explanation for immortalization, epigenetic alterations causing a d eterministic process of dedifferentiation in a subpopulation of the ce lls appear as plausible or perhaps even more plausible as a probabilis tic mutation. This indicates that disturbance of differentiation might be among the causes of genetic instability.