Epigenetic events during the process of cell transformation induced by carcinogens (review)

Recent studies clearly demonstrate that several environmental carcinogens l ack the ability to initially induce genetic damage. In that view, multistag e chemical carcinogenesis may be processed under the control of a variety o f epigenetic events in addition to genotoxic impacts. The understanding of this mechanism as reviewed in this report requires knowledge of early chang es induced by carcinogens in target cells, biochemical, biological and mole cular reactions closely related to both sides of the growth equation: cell proliferation and programmed death. Among several cell transformation model s, the most suitable for carcinogen detection and mechanistic study is the Syrian hamster embryo (SHE) cell transformation assay. This closely mimics the multistage carcinogenesis and eve can examine, in a relatively short ti me (8 days), the mechanisms by which genotoxic and non-genotoxic agents may increase the frequency of cell transformation as a preneoplastic end-point . The mode of action of hundred of compounds, carcinogens and noncarcinogen s, has been explored so far using one-stage and two-stage treatment protoco ls. In general, with the two-stage protocol, all carcinogens, irrespective of their genotoxic or non-genotoxic potential, give unambiguous positive re sults. Since perturbations of cell proliferation and death are considered e ssential events in the process of carcinogenesis, studies have been conduct ed on the dysregulation of two specific parameters, the induction of ornith ine decarboxylase (ODC) an enzyme related to cell proliferation, and the ap optosis rate, when SHE cells are exposed to carcinogens. In one-stage treat ment (5 h-24 h), only the promoter TPA induces ODC activity, while other ca rcinogens do not increase this activity. Using the two-stage exposure proto col (1 h xenobiotic/5 h TPA), all carcinogens both genotoxic and non-genoto xic, are able to stimulate ODC activity above the level obtained with TPA a lone. Based on the two-stage treatment with carcinogens a close relationshi p can be obtained between the ODC superinduction and the increase of morpho logical cell transformation frequency. In cancer development, it is postula ted that the inhibition of apoptosis may help altered cells to escape cell death and acquire a tumorigenic phenotype. Two-stage treatment carcinogen/T PA, effectively decreases the apoptotic rate. This is accompanied by an upr egulation of the Bcl-2 oncoprotein, a well-known apoptotic inhibitor. Howev er, treatment with a non-carcinogen phthalic anhydride, also inhibits apopt osis while it does not superinduce ODC activity. Although inhibition of apo ptosis is not specific to the carcinogenic compound, both superinduction of ODC activity and inhibition of apoptosis via Bcl-2 upregulation may cooper ate during the early stages of the carcinogenic process. In a long-term sta ge transformation assay, the rate of transformed colonies is relatively low (2-8%) bringing about the slow evolution of tumoral disease in humans and tumoral induction in rodents. This could be the consequence of the activati on of various cellular repair mechanisms during the exposure time. Experime ntal data reported so far point out that genotoxic and non-genotoxic carcin ogens, thought to be more active in the initiation or in the promotion stag e, must share the same stage pathway leading to cancer development.