The role of receptors in multistage carcinogenesis

The principal characteristic of neoplasia is its inherited alteration of genetic expression. The regulation of gene expression may be altered both by mutational events and by environmental mediators. During carcinogenesis the permanent alterations in genetic expression resulting from mutations occur primarily during the final stage of progression when biological malignancy becomes evident. During the preceding reversible stage of promotion, alteration and genetic expression are the result of the chronic stimulation of an altered (initiated) cell responding to the environmental mediator or promoting agent. A major mechanism of this effect occurs by receptors exhibiting specificity for the mediator and for their interaction with the genome. Withdrawal of the promoting agent prior to the genetic alterations characteristic of the stage of progression leads to a reversal of the effects of the promoting agent and the death by apoptosis of most cells in the stage of promotion. Carcinogenesis mediated by the chronic ligand (promoting agent)-receptor interaction increases the probability of the development of the stage of progression; thus alteration or prevention of the stage of promotion by removal of the promoting agent or inhibition of its action remains the best opportunity for cancer prevention. Application of the reversible promoting agent-receptor interaction to specific environmental circumstances where such plays a major role can lead to a more rational risk estimation of promoting agents for the human population.