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Protein Kinase C- Transgenic Mice: A Unique Model for Metastatic Squamous Cell Carcinoma¹

Departments of Human Oncology [A. P. J., N. E. D., D. L. W., A. K. V.] and Pathology and Laboratory Medicine [E. G. V., T. D. O.], Medical School, University of Wisconsin, Madison, Wisconsin 53792, and Veterans Administration Hospital [T. D. O.], Madison, Wisconsin 53705

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common forms of human skin cancer. BCC is slow growing and mostly localized, whereas SCC metastasizes to the regional lymph nodes and subsequently to distal organs. In murine skin carcinogenesis models for SCC, the incidence of metastasis is very low. We report here that FVB/N transgenic mice, which overexpress (18-fold) epitope-tagged protein kinase C- (T7-PKC) protein in the epidermis provide a unique murine model system for highly malignant/metastatic SCC. Skin tumors were developed by the initiation-promotion protocol (initiation with 100 nmol 7,12-dimethyl-benz[a]anthracene; promotion with 5 nmol 12-O-tetradecanoylphorbol-13-acetate twice weekly). T7-PKC transgenic mice showed 92% suppression of papilloma development compared with wild-type littermates after 23 weeks of tumor promotion. However, within 15–20 weeks of 12-O-tetradecanoylphorbol-13-acetate promotion, 40% of T7-PKC mice developed at least one carcinoma compared with 7% of the wild-type mice. All carcinomas from T7-PKC mice appeared without prior papilloma formation. Interestingly, 7,12-dimethyl-benz[a]anthracene alone resulted in the development of squamous cell carcinomas in 22% of T7-PKC mice, whereas wild-type littermates developed no tumors. Histopathological analysis of tumors from multiple T7-PKC mice revealed moderately differentiated SCC invading the dermal region with neoplasia appearing to originate and invade from the hair follicle. Carcinomas of T7-PKC mice rapidly metastasized to regional lymph nodes within 3 weeks of appearance. In wild-type mice, the grade of the invading tumors, originating from interfollicular epidermis, was pathologically categorized as well-differentiated SCC and remained localized to the dermis. The T7-PKC transgenic mice may provide a rapid and unique in vivo model to investigate metastatic SCC.

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