12-O-tetradecanoylphorbol-13-acetate-mediated systemic co-promotion in the murine skin multistage carcinogenesis protocol.

The systemic promoting and co-promoting activities of 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined in a murine skin multistage carcinogenesis protocol. The dorsal skins of female inbred SENCAR (SSIN) mice were initiated with 25 nmol of 7,12-dimethylbenz[a]anthracene (DMBA). Topical treatment of initiated dorsal skin with 20 mg of benzoyl peroxide (BzP) promoted the eventual development of 8-15 dorsal papillomas per mouse. Repeated application of 2 micrograms of TPA to the ventral skins of dorsally initiated mice did not promote the formation of dorsal tumors. However, the latency of dorsal papilloma development was significantly decreased in initiated mice treated with 0.4 or 2 micrograms TPA (ventral application) and promoted with BzP (dorsal application). The co-promoting effects of topically applied TPA could not be mimicked by administering the promoter i.v. Only 6/23 initiated, BzP-promoted SSIN mice developed squamous cell carcinomas (SCC) during a 61 week promotion period. In contrast, during the same time-frame 12/24 and 11/24 BzP-promoted mice cotreated with 2 or 0.4 microgram of TPA developed SCC respectively. Repeated application of 2 micrograms of TPA to the ventral skins of dorsally initiated mice resulted in the development of ventral tumors. Ventral tumor incidence and multiplicities could be dramatically reduced by housing the mice individually, as opposed to collectively, for a day following initiation. Collectively these findings suggest that TPA can function as a co-promoter in the murine skin multistage carcinogenesis model through a systemic mechanism. The systemic co-promoting activity may be mediated by a factor(s) produced by the skin in response to TPA exposure. Furthermore, inter-mouse transfer of topically applied initiator from one cutaneous site to another occurs as a consequence of the huddling habits of mice.