Protein kinase C-epsilon transgenic mice: A unique model for metastatic squamous cell carcinoma

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most c ommon forms of human skin cancer. BCC is slow growing and mostly localized, whereas SCC metastasizes to the regional lymph nodes and subsequently to d istal organs. In murine skin carcinogenesis models for SCC, the incidence o f metastasis is very low. We report here that FVB/N transgenic mice, which overexpress (similar to 18-fold) epitope-tagged protein kinase C-epsilon (T 7-PKC epsilon) protein in the epidermis provide a unique murine model syste m for highly malignant/metastatic SCC. Skin tumors were developed by the in itiation-promotion protocol (initiation with 100 nmol 7,12-dimethyl-benz[a] anthracene; promotion with 5 nmol 12-O-tetradecanoylphorbol-13-acetate twic e weekly). T7-PKCe transgenic mice showed 92% suppression of papilloma deve lopment compared with wildtype littermates after 23 weeks of tumor promotio n. However, within 15-20 weeks of 12-O-tetradecanoylphorhol-13-acetate prom otion, 40% of T7-PKC epsilon mice developed at least one carcinoma compared with 7% of the wild-type mice. All carcinomas from T7-PKCe mice appeared w ithout prior papilloma formation. Interestingly, 7,12-dimethyl-benz[a]anthr acene alone resulted in the development of squamous cell carcinomas in 22% of T7-PKC epsilon mice, whereas wild-type littermates developed no tumors. Histopathological analysis of tumors from multiple T7-PKC epsilon mice reve aled moderately differentiated SCC invading the dermal region with neoplasi a appearing to originate and invade from the hair follicle. Carcinomas of T 7-PKC epsilon mice rapidly metastasized to regional lymph nodes within 3 we eks of appearance. In wild-type mice, the grade of the invading tumors, ori ginating from interfollicular epidermis, was pathologically categorized as well-differentiated SCC and remained localized to the dermis, The T7-PKC ep silon transgenic mice may provide a rapid and unique in vivo model to inves tigate metastatic SCC.