Malignant Conversion, the First Stage in Progression, is Distinct from Phorbol Ester Promotion in Mouse Skin

Abstract

Multiple stages in the induction of benign and malignant tumors have been demonstrated experimentally in the mouse skin model system of chemical carcinogenesis^1,2. Although skin tumors can be induced by repeated topical applications of a carcinogen³, protocols have been developed which define at least three distinct stages: initiation, promotion and malignant conversion^4–6. In a typical experiment, the first stage, initiation, is accomplished by a single exposure to a low dose of a mutagenic carcinogen. Initiation, which may represent a single mutational event⁷, causes a heritable change in some epidermal cells, which are termed “initiated.” Without subsequent treatment, the initiated cells do not develop into tumors. Repeated topical treatment of initiated mice with a tumor promoter allows the expression of the neoplastic change resulting in the formation of benign squamous papillomas. The second stage, promotion, is effective even when promoter treatments are delayed for several months after initiation, indicating the irreversibility of the initiating mutation. In contrast, the promoting effects of individual TPA applications are reversible since papillomas do not develop after insufficient exposure of initiated skin to promoters or when the interval between individual promoter applications is increased. The reversibility of promotion suggests an epigenetic mechanism. Promotion can be defined as the selective clonal expansion of initiated cells.