Regulation of tumor angiogenesis and metastasis, and postischemic angiogenesis by sphingosine-1-phosphate signaling system

鞘氨醇-1-磷酸受体S1PR2是第一个G蛋白偶联受体，通过抑制G12/13-Rho下游的Rac负向调节细胞迁移。肿瘤细胞表达的S1PR2在体外可抑制细胞的迁移和侵袭，在体内可抑制血道转移。S1PR2在宿主血管内皮细胞和骨髓来源的髓系细胞中表达，共同介导体内肿瘤血管生成和肿瘤生长的抑制。我们研究了宿主S1PR2在转移和缺血后血管生成中的作用，并发现了有趣的结果。我们还通过比较SphK1转基因小鼠和它们的后代的恶性肿瘤发病率，测试了一个被广泛接受的概念，即SphK1是一种主要的S1P合成酶，在癌症的发生中起到了致病作用。我们发现，在SphK1转基因小鼠和小鼠野生型小鼠之间，自发或ENU(一种诱变剂)诱导的肿瘤发展的发生率没有差异。

The sphingosine-1-phosphate receptor S1PR2 is the first G protein-coupled receptor that negatively regulates cell migration through inhibition of Rac downstream of G12/13-Rho. S1PR2 expressed in tumor cells mediates inhibition of cell migration and invasion in vitro and hematogenous metastasis in vivo. S1PR2 expressed in host vascular endothelial cells and bone marrow-derived myeloid cells together mediate inhibition of tumor angiogenesis and tumor growth in vivo. We studied the roles of host S1PR2 in metastasis and post-ischemic angiogenesis and found interesting results. We also tested a widely accepted concept that sphingosine kinase 1 (SphK1), a major S1P synthesizing enzyme, plays an causative role in cancer development, by comparing incidence of malignancies between SphK1 transgenic mice and their littermates. We found no difference in incidence of either spontaneous or ENU (a mutagen)-induced tumor development between SphK1 transgenic and littermate wild type mice.