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Immortalization of Syrian Hamster Embryo Cells: Probabilistic Event or Deterministic Process¹

MGC-Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, The Netherlands

Previous findings on the induction of immortalization in SHE cells have been explained with the activation/alteration hypothesis which postulates that treatment with a carcinogen results in the induction of a so-called "activated state" which enhances the rate of a probabilistic event in the progeny of the treated cells. This event is supposed to be a mutation. Because it has been recently indicated that in mammalian cells the switching on of signal transduction pathways by 12-O-tetradecanoyl-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 in 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 confluence 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 program.

Treatment with benzo(a)pyrene also interferes with the life span resulting in premature senescence in most of the cells and extension of life span in a small fraction of the cells which subsequently can become immortal.

Repeated switching from logarithmic growth to G₀ also enhanced life span and rate of immortalization.

The findings indicate that the activated state is a disturbance of a differentiation program affecting in SHE cells the program of cellular senescence and that, as an explanation for immortalization, epigenetic alterations causing a deterministic process of dedifferentiation in a subpopulation of the cells appear as plausible or perhaps even more plausible as a probabilistic mutation. This indicates that disturbance of differentiation might be among the causes of genetic instability.

¹ This paper is the third in a series on immortalization. The research was supported by the Dutch Cancer Foundation, Grant IKW 87-4, by the J. A. Cohen Institute for Radiopathology and Radiation Protection, and by contract B-16-E-141-NL and F13P-CT92-0028 of the Association between the European Community with the University of Leiden.

² To whom requests for reprints should be addressed.

Received 2/12/93. Accepted 8/ 6/93.