Biological and molecular aspects of radiation carcinogenesis in mouse skin.

The process of mouse skin carcinogenesis can be operationally subdivided into at least three stages which have been termed initiation, promotion, and progression. Ionizing radiation has been found to be a weak initiator of malignant squamous cell carcinomas (SCCs) when radiation was followed by repeated treatments of the skin with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Besides SCCs, ionizing radiation was found to induce, independent of tumor promoters, basal cell carcinomas (BCCs), a tumor histology not normally seen with chemical carcinogens and mouse skin. Fractionated doses of 1 MeV electrons were found to enhance the conversion of chemically induced benign papillomas to malignant SCCs. In addition to the biological studies, questions related to dominant transforming genes and differential gene expression in the radiation-initiated mouse skin tumors have been explored. Distinct non-ras dominant transforming gene(s) have been detected in radiation-initiated, TPA-promoted SCCs. Differences in the expression pattern of tumor-associated genes were seen in comparing chemically to radiation-induced benign and malignant skin tumors. Therefore, ionizing radiation has been shown to be active in the initiation of malignant skin tumors and progression of benign to malignant tumors in the mouse skin. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin model has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation-versus chemically induced tumor development.