Relative to TPA promoted controls, intraperitoneal administration of recombinant DNA-derived murine gamma interferon (rMuIFN-gamma) to DMBA initiated mice within 24h of TPA promotion, elevated papilloma multiplicities and accelerated the progression of papillomas into carcinomas. Since treatment of initiated mice with only rMuIFN-gamma did not promote the development of any skin tumors, it functioned as a copromoter with TPA. A model for IFN-gamma action consistent with our data is that copromotion and accelerated tumor progression are a consequence of IFN-gamma dependent macrophage activation which results in amplification of a TPA triggered respiratory burst in cutaneous macrophages. To test this hypothesis and further characterize the phenomenon of IFN-gamma dependent copromotion we will determine whether conditions facilitating copromotion actually amplify the respiratory burst of TPA-stimulated macrophages and whether measurements or vascular permeability and ornithine decarboxylase can be used as short term diagnostics of copromotion the murine skin multistage carcinogenesis model will be used to determine: a) whether macrophage activation is required for copromotion; and b) if IFN-gamma can function as a copromoter with non-phorbol ester tumor promoting agents; and c) if IFN-gamma can facilitate the progression of papillomas into carcinomas in the absence of TPA. Lastly, papilloma multiplicities in TPA promoted mice and mice receiving TPA plus macrophages isolated from mice activated in vivo with IFN-gamma will be compared to directly assess the role of macrophages in mediating copromotion. These studies have human health relevance due to the therapeutic and prophylactic uses of IFNs. Furthermore, they are novel because they clearly demonstrate the concept of copromotion and suggest that chemically induced skin cancer can be effected through systemic modulation of components of the immune system.
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