We are using a v-Ha-ras transgenic mouse model which rapidly develops large numbers of epidermal papillomas following 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, to study the events of tumorigenesis associated with ras activation. Using the techniques of Western blotting, polymerizing chain reaction, and in situ hybridization we have localized and quantitated transgenic ras mRNA and protein product expression in both benign and malignant skin tumors, as well as odontogenic and mammary tumors. The transgene is expressed in the basal epidermal cells of the papillomas but not in normal or non-tumor bearing TPA-treated skin. Immunohistochemical analysis for PCNA (proliferating cell nuclear antigen), which is a marker for dividing cells, localizes the proliferating cells of the papillomas to this same basal epidermoid cell population. Thus, the transgene expressing cells are also the proliferating component of the papillomas. At timepoints before the appearance of papillomas, we have also identified focal hyperplasias of the follicular epidermis which we hypothesize are the precursors of the epidermal papillomas. Supporting this observation are recent experiments in which we have shown that depilation by plucking is alone sufficient to cause papilloma formation in the TG.AC mice. Current research is dedicated to testing the hypothesis that the papillomas arise from stem cells located in the follicular epidermis. As a result of this work, we believe that the TG.AC mice will prove to be a very useful model for studying very early events in papillomagenesis.
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