Molecular mechanisums for S1P_2 G protein coupled receptor-mediated inhibition of tumor progression

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Plasma-derived lipid mediator sphingosine- 1-phosphate (S1P) acts via the G protein-coupled SIP receptor family to regulate a variety of physiological and pathological responses. S1P_1 receptor mediates endothelial cell migration and vascular maturation, promoting vascular integrity. We have previously shown that S1P_2R is distinct from SlP_1R in that it negatively regulates cell migration and endothelial capillary tube formation hi vitro. In the present study we investigated the role of host cell S1P_2R in tumor growth and angiogenesis by comparing S1P_2 knock out (KO) and their wild type (WT) littermate mice. Lewis lung carcinoma cells and B16BL6 melanoma cells were subcutaneously injected to S1P_2KO and WT mice and allowed to grow for 3 weeks. Tumors of either cell type grew substantially more rapidly in S1P_2KO as compared with WT mice. Tumors in S1P_2KO mice displayed significant increases in the number of blood vessels, blood vessel cross sectional area and association of desmin-positive mural cells around the tumor vessels. Leakage of intravenously injected FITC-dextran per a unit area of tumor was increased in S1P_2KO compared with WT mice, in part because of increased numbers of vessels. Tumors in S1P_2KO mice also showed upregulation of angiogenic factors including VEGF-A, Notch ligand Delta-like ligand 4 and TGFβ1. The results indicate that host cell S1P_2R negatively regulates tumor growth and angiogenesis in vivo, with inhibition of angiogenic gene expression and mural cell recruitment. Selective activation of S1P_2R would be a promising novel anti-tumor therapeutic strategy.