Several genes and markers involved in the initiation, promotion, and malignant conversion of skin tumors have been investigated in mouse skin and in keratinocyte culture. Normal keratinocytes in culture initiated by infection with a retrovirus encoding the v-rasHa oncogene resist terminal differentiation signals and produce benign papillomas when grafted to the backs of athymic mice. In contrast, grafts of v-rasHa-initiated keratinocytes with a null mutation in either transforming growth factor (TGF)-beta1 or p53 formed squamous cell carcinomas. Further studies indicated that the loss of autocrine TGF-beta1 may contribute to malignant progression by decreasing genomic stability. TGFalpha is not essential for epidermal neoplasia induced by the v- rasHa oncogene, but the epidermal growth factor (EGF) receptor can mediate the rate of tumor growth. Promotion of c-fos knockout mice induced papillomas that failed to convert to malignancy, indicating a role for fos in malignant conversion. A number of genes regulated by fos and/or AP-1 have been identified in papillomas with high or low risk of conversion to malignancy. The overexpression of ornithine decarboxylase by itself is insufficient to induce tumors, but increased expression enhances tumor development in initiated keratinocytes. Caffeic acid phenethyl ester, an inhibitor of skin tumor promotion, is selectively toxic for papilloma cells. Retinoic acid inhibited the promotion of papillomas, and suppressed the progression to malignancy in the papillomas that did develop. Genetic analysis of the genes responsible for determining susceptibility to skin carcinogenesis indicated that critical genes are located on mouse chromosomes 5, 8 and 9.
