Cutaneous chemical carcinogenesis

This review is designed to inform the clinician of current concepts regarding the pathogenesis of chemically induced skin cancer. Chemicals induce cutaneous cancers in a wide variety of experimental animals and in humans. The most common benign experimental tumors are papillomas and keratoacanthomas, whereas common malignancies are squamous cell carcinomas and melanomas. Carcinoma development is a multistage process that involves at least three mechanistically distinct steps. Initiation is the earliest change in an epidermal cell exposed to carcinogens such as polycyclic aromatic hydrocarbons, alkylating agents, or nitrosamines. This stage appears to result from carcinogen-induced deoxyribonucleic acid damage leading to a mutation-like genetic change. Only a limited number of epidermal genes may be changed to yield the initiated cell, and one has been identified as the Harvey ras gene, a gene involved in epidermal proliferation. Initiated epidermal cells are not malignant but are insensitive to the normal signals for terminal differentiation in the epidermis. The second stage, tumor promotion, results from repeated exposure of initiated skin to one of a variety of noncarcinogenic promoting agents such as phorbol esters, benzoyl peroxide, anthralin, or certain halogenated aromatic hydrocarbons. Some promoters require specific cellular receptors and produce transient changes in the growth or differentiation of the epidermis. Collectively these agents produce a tissue environment that is conducive to the selective clonal outgrowth of the initiated cell population, resulting in a clinically apparent premalignant tumor. During the third stage of carcinogenesis, premalignant cells are converted to malignancy. This step may occur spontaneously, but the frequency is greatly enhanced by exposure to mutagens, including several initiating agents. Thus malignant conversion is likely due to additional mutations in a benign tumor cell. The Harvey ras gene may also be a potential target in the conversion step. Several agents, such as corticosteroids and retinoids, have been identified as anticarcinogens for skin. They appear to be primarily antipromoting agents and could have important clinical applications. Melanomas can be induced in several species by repeated exposure to initiators or by exposure to an initiator and a tumor promoter. The experimental pathogenesis of this tumor is unclear. It is proposed that intermediates in the synthesis of melanin pigment could act as endogenous carcinogens or promoters in melanoma development. Increased awareness of the mechanisms of chemical carcinogenesis in skin will enhance cancer prevention in this tissue. Furthermore, astute clinical observations are essential for identifying new human carcinogens and for extrapolating experimental concepts to greater understanding of the development of skin cancers in patients.