251 Selective blockade of phosphatidylinositol-3 kinaseγ suppresses the development of cutaneous squamous cell carcinoma

Phosphatidylinositol-3 kinase (PI3K) is one of the major factors in the signaling pathway that regulates cell growth, survival, metabolism, and migration via the downstream AKT/mTOR pathway. Mutations that constitutively activate the PI3K/AKT/mTOR pathway occur most frequently in human cancers. PI3Kγ, which has p110γ as its catalytic domain, is expressed on innate immune cells such as macrophages and dendritic cells. Recently, PI3Kγ has been shown to act as a molecular switch that regulates the differentiation of M1 macrophages into tumor associated macrophages (TAM). Mutations in PI3Ka are found in many cancers, including cutaneous squamous cell carcinoma (cSCC). However, the functions of other PI3K isoforms in skin cancer are not known. In this study, we generated p110γ knockout mice and analyzed their function in cSCC development. First, we performed a two-step chemical carcinogenesis experiment in which DMBA-TPA was applied to the back skin of mice. Whereas wild-type mice formed papillomas, keratoacanthomas, and cSCCs at high frequency, carcinogenesis was markedly suppressed in p110γ KO mice, even though p110γ is barely expressed in the epidermis. In fact, treatment of cultured epidermal cells with p110γ inhibitors did not suppress proliferation. When a cell line was established from cSCCs produced by chemical carcinogenesis and injected subcutaneously into mice of the same strain, cSCC formation was markedly suppressed in p110γ KO mice. The p110γ KO mice inoculated with cSCC cells showed a marked decrease in TAMs. These results indicate that p110γ enhances cSCC development by promoting TAM differentiation. These results suggest that an inhibitor of p110γ could be a potential therapeutic agent for cSCC.