Inversion of carcinogen-promoter sequence: effects on mouse skin tumorigenesis and cellular growth kinetics

To stimulate conditions wherein humans might be exposed to tumor promoters prior to carcinogenic stimulus, female S/RV Cri mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 10 weeks followed by a sc injection of 3-methylcholanthrene (MCA). Six weeks after MCA administration, tissue alterations in different skin layers were analysed by histology, morphometry and autoradiography. Multiple application of TPA prior to MCA injection induced moderate to marked epidermal hyperplasia with an increase in the thickness of nucleated cell layers and stratum granulosum. As compared to control, number of basal and suprabasal cells per 7.5 mm of interfollicular epidermal (IFE) length was significantly higher in the skin of animals treated with TPA + MCA. The hyperplastic response was accompanied by a significant increase in epidermal mitotic activity, number of cells in DNA-synthetic phase in epidermis, dermis and subcutis and subepidermal mast cell population. Histological observations of induced tumors revealed a significant increase in the incidence of carcinomas and mixed neoplasms of epithelial and mesenchymal histogenesis. The findings suggest that stimulated cellular proliferation in different layers of mouse skin by TPA treatment prior to MCA injection may play a major role in enhanced expression of histogenetically distinct tumors.