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

鞘氨醇-1-磷酸受体S1 PR 2是第一个G蛋白偶联受体，其通过抑制G12/13-Rho下游的Rac来负调节细胞迁移。S1 PR 2在肿瘤细胞中表达，介导体外细胞迁移和侵袭的抑制以及体内血行转移的抑制。S1 PR 2在宿主血管内皮细胞和骨髓源性髓样细胞中表达，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S1 PR 2在转移和缺血后血管生成中的作用，发现了有趣的结果。我们还测试了一个广泛接受的概念，即鞘氨醇激酶1（SphK 1），一种主要的S1 P合成酶，在癌症发展中起着致病作用，通过比较SphK 1转基因小鼠和它们的同窝仔之间的恶性肿瘤的发病率。我们发现SphK 1转基因小鼠和同窝野生型小鼠之间自发或ENU（一种诱变剂）诱导的肿瘤发生率无差异。

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.