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

血浆来源的脂质介质鞘氨醇-1-磷酸（S1 P）通过G蛋白偶联的SIP受体家族发挥作用，以调节各种生理和病理反应。S1P_1受体介导内皮细胞迁移和血管成熟，促进血管完整性。我们以前的研究表明S1P_2R与S1P_1R的不同之处在于它在体外负性调节细胞迁移和内皮毛细血管的形成。本研究通过比较S1P_2基因敲除（KO）和野生型（WT）同窝小鼠，研究了宿主细胞S1P_2R在肿瘤生长和血管生成中的作用。将刘易斯肺癌细胞和B16 BL 6黑色素瘤细胞皮下注射到S1 P_2 KO和WT小鼠中，并使其生长3周。与WT小鼠相比，任一细胞类型的肿瘤在S1P_2KO中生长得更快。S1P_2KO小鼠肿瘤血管数目、血管截面积和结蛋白阳性壁细胞在肿瘤血管周围的结合显著增加。与WT小鼠相比，S1P_2 KO小鼠每单位面积肿瘤静脉注射的FITC-葡聚糖渗漏增加，部分原因是血管数量增加。S1P_2KO小鼠的肿瘤也显示血管生成因子包括VEGF-A、Notch配体Delta样配体4和TGFβ1的上调。结果表明，宿主细胞S1P_2R通过抑制血管生成基因的表达和壁细胞的募集，负调控肿瘤的生长和血管生成。选择性激活S1 P2 R可能是一种新的抗肿瘤治疗策略。

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.