Blmc. Bols et al., IMMORTALIZATION OF SYRIAN-HAMSTER EMBRYO CELLS - PROBABILISTIC EVENT OR DETERMINISTIC PROCESS, Cancer research, 53(20), 1993, pp. 4797-4802
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.