Mechanisms of initiation and promotion in mouse epidermis

Studies performed on mouse skin have indicated that chemical carcinogenesis can be subdivided into two distinct stages--initiation and promotion. Initiation results from exposure to a classical mutagenic carcinogen and is irreversible even after a single exposure. The permanently altered initiated cell and its progeny may never form a tumour or be in any way recognizable in the target tissue. Exposure to tumour promoters permits the expression of the neoplastic change in initiated cells, and tumours develop. In contrast to initiators, promoters must be given repeatedly to be effective; individual exposures are reversible. Studies in mouse skin cell cultures have provided new insights into the changes associated with initiation and promotion. Some carcinogen-treated cells and cells derived from initiated mouse skin are resistant to signals for terminal differentiation and can proliferate under conditions in which normal cells are obliged to cease proliferation and begin their maturation programme. This change is essential for a tumour cell, since it provides it with the ability to grow away from a basement membrane attachment site. In cultured epidermal cells, tumour promoters are capable of stimulating selectively the growth of certain cells, including initiated cells, while inducing simultaneously terminal differentiation in other epidermal cells. The induction of terminal differentiation may be mediated by the phorbol ester receptor. The net effect of these responses to promoters is the clonal expansion of cells stimulated to proliferate. In this way, promoters are capable of increasing the clone size of initiated cells and producing benign tumours. In-vivo studies have indicated that promoters are incapable of accelerating the conversion of benign to malignant tumours. However, exposure of papilloma-bearing mice to genotoxic initiating carcinogens accelerates malignant conversion markedly. Thus, initiation and promotion appear to be relevant to the formation of preneoplastic lesions, but further genetic damage may be required for the carcinogenic event.