Abstract
TPA, which is a potent promoter of mouse epidermal carcinogenesis, is inactive as a promoter on hamster, rat, and guinea pig skin. In order to probe the basis for this species specificity, the effects of TPA on hamster epidermis and hamster epidermal cells in culture were studied and compared to the known effects of TPA on mouse skin. We first wanted to determine whether TPA was reaching the target cells or if it was metabolized. Our studies revealed that metabolic inactivation of TPA does not account for its lack of tumor promoting activity on hamster skin. In addition, hamster epidermis treated with 81 nmol of TPA responded in a manner analogous to TPA-treaLed mouse epidermis. A hyperplastic response of the hamster skin was observed reaching a maximum at 48 hours after TPA treatment. Ultrastructural changes similar to those induced in mouse skin by TPA were observed in hamster skin. Hamster epidermal cells grown in culture also responded to TPA. TPA inhibited terminal differentiation of hamster epidermal cells and stimulated DNA synthesis in the cultures. These results demonstrate that TPA is very active on hamster epidermis and epidermal cells in culture. Since tumor promotion requires long–term exposure of cells to TPA and all the above experiments were acute experiments, the effects on hamster epidermis of TPA treatment for 1 to 4 weeks were studied. The most significant difference between mouse and hamster skin is in their hyperplastic response to TPA. In the mouse there is a potentiation in TPA-induced hyperplasia after two or more exposures to the promoter; while hamster skin adapts to the TPA treatment and no longer responds hyperplastically after multiple doses. The mechanism of this adaptation is unknown, but is currently under investigation. Examining differences in adapted and nonadapted hamster skin should be useful in understanding the mechanism of TPA promoting action. The role of sustained hyperplasia in tumor promotion and current models of tumor promotion are discussed.
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