Evolving perspectives on the biology and mechanisms of carcinogenesis

Abstract

From experimental and epidemiological evidence, radiation-induced cancers appear to arise as multistage, monoclonal growths, which are elicited through various mechanisms, depending on the neoplasm in question and the conditions of exposure. At the molecular level, the process of carcinogenesis may involve the activation of oncogenes and/or the inactivation or loss of anti-oncogenes, through chromosomal rearrangements, point mutations, and other effects of radiation on DNA. In contrast to these mechanisms of carcinogenesis, which result from the absorption of radiation by the tumor-forming cells themselves, abscopal effects resulting from irradiation of other cells may contribute to carcinogenesis under certain conditions, e.g. in the induction of tumors of endocrine target cells through radiation-induced disturbances of hormonal balance. Effects of the latter type, which require the killing of substantial numbers of cells, are not elicited at low doses, thus contrasting with effects of the former type, which may be presumed to have no thresholds. Because radiation carcinogenesis may be mediated through a diversity of effects, the relationship between incidence and dose can vary accordingly. The relationship between the incidence of radiation-induced tumors and the time elapsing after irradiation also varies, depending on the type of tumor in question, species, age at irradiation, exposure conditions, and other factors. Although the variations with dose and time are consistent with multistage models of tumor initiation, tumor promotion, and tumor progression, the precise nature of the successive steps that are involved remains to be determined. The tendency for the tumors to resemble their spontaneous counterparts in age-distribution points to interactions between radiation and other carcinogenic risk factors which are as yet poorly understood. Also poorly understood are species- and organ-differences in susceptibility to radiation carcinogenesis, which bear no consistent relationship to corresponding ‘spontaneous’ cancer rates.