[Carcinogenesis: from epidemiology to molecular biology]

Carcinogenesis is a multi-step process and at least three stages can be distinguished: initiation, promotion and progression. Initiation is made up of events whereby an exogenous or endogenous carcinogen induces alterations in the genome of the cell; this results in a lesion that can be inherited and which confers upon that cell the potential for neoplastic growth. This is the result of activation of cellular proto-oncogenes into transforming oncogenes and/or the inactivation of the two alleles of tumor suppressor genes (anti-oncogenes). Although it is conceivable that a single event or a single lesion can initiate a cell it is probable that in most cases initiation is the consequence of a series of events since the different types of proto-oncogenes do not function independently of each other. The coordinated activation of more than one oncogene is generally required to confer the full potential for neoplastic growth. DNA repair and apoptosis play a critical role in carcinogenesis and the effectiveness of these mechanisms might be influenced by the dose and the time interval between individual events (dose rate). Epidemiological and experimental data show also the main role of cell proliferation after initiation. Proliferation influences the probability of DNA repair and contributes to further genomic alteration. Cell to cell interaction within a tissue participates in the control of cell proliferation and cell repair. The evolution of one initiated cell is not independent of the surrounding cells and disorganization of a tissue is a factor in carcinogenesis. Presently carcinogenesis appears to be a complex phenomenon which cannot be a adequately modelled. The linear no-threshold model has been used for the purpose of cancer prevention and legal norms, however it should be realized that its experimental and theoretical bases are debatable and that much recent data do not support them. Its predictions should therefore be considered with great caution. All efforts should be made in the future to build new models incorporating available epidemiological and fundamental data.