A model for initiated mouse skin: suppression of papilloma but not carcinoma formation by normal epidermal cells in grafts on athymic nude mice.

The availability of a skin grafting system on nude mouse hosts and of epidermal cell lines which form papillomas when grafted has made possible the creation of a model for initiated skin in vivo from cultured cells. When grafted with 6-8 x 10(6) primary dermal fibroblasts, 10 x 10(6) primary epidermal cells form an apparently normal skin, and cell line SP-1 (0.5 x 10(6) cells) forms papillomas. Cell line SP-1 was derived from papillomas produced on SENCAR mice by initiation with 7,12-dimethylbenzaadaa]anthracene and promotion with 12-O-tetradecanoylphorbol-13-acetate. Grafting of 0.5 x 10(6) SP-1 cells along with 10 x 10(6) SENCAR newborn primary epidermal cells resulted in a 90% reduction in the average papilloma volume per mouse compared to controls without primary epidermal cells. Suppression occurred specifically with epidermal cells, either cultured or freshly prepared, and was not seen when an equivalent number of SENCAR primary dermal fibroblasts was grafted in place of epidermal cells. Nor did suppression occur when primary epidermal cells were replaced with a carcinogen-altered cell line, SCR722. SCR722 cells have a normal-skin phenotype when grafted. Furthermore, suppression of tumor formation did not occur when a malignant variant of SP-1 cells replaced benign SP-1 cells in grafts. Repeated treatment of suppressed grafts with 12-O-tetradecanoylphorbol-13-acetate resulted in an increased number of mice with papillomas and a larger mean papilloma volume per mouse compared to controls treated with solvent alone, whereas treatment of nonsuppressed grafts of papilloma cells with promoter produced no change in tumor size. These results support the concepts that normal epidermal cells suppress the growth of initiated cells and that repeated treatment with phorbol ester tumor promoters overcomes the suppression, leading to benign tumor formation.