第82回日本生化学会 2009年10月21-24日(神戸)
腫瘍血管新生におけるスフィンゴシンー1 −リン酸受容体S1P2 の役割
Wa Du, 多久和典子, 吉岡和晃, 岡本安雄, Xun Qi, Fei Wang, Hong Cui, Kuntal Biswas, 杉原一
司, 浅野雅秀, 多久和陽 
 

ABSTRACT

Sphingosine-1-phosphate (S1P) has pleiotropic activities including the regulation of cell motility, actin cytoskeleton, and cell proliferation via three major widely expressed G protein-coupled receptors, S1P1, S1P2 and S1P3. S1P has been implicated in tumor angiogenesis by acting via a Gi-coupled chemotactic receptor S1P1 which is expressed in vascular endothelial cells. Distinctly from S1P1, S1P2 mediates S1P inhibition of Rac and cell migration via G12/13 and the Rho pathway. The detailed expression of S1P2 in vascular cells and its role in tumor angiogenesis remained unknown. By using S1P2( LacZ/+) mice, we found that S1P2 was expressed in normal blood vessels in many organs and tumor vessels in both endothelial cells (ECs) and VSMCs, as well as tumor-associated, CD11b-positive bone marrow-derived cells (BMDCs). Lewis lung carcinoma (LLC) and B16BL6 melanoma tumors implanted in S1P2-deficient (S1P2-/-) mice showed accelerated tumor growth, stimulated angiogenesis with enhanced association of vascular mural cells, and increased recruitment of CD11b-positive BMDCs, compared with tumors in S1P2-/- siblings. Compared with S1P2+/+ ECs, S1P2-/- ECs showed enhanced Rac activity, cell migration, proliferation and tube formation in vitro, and promotion of tumor growth and angiogenesis in vivo when co-injected with tumor cells into S1P2+/+ mice. The bone marrow transplantation experiments showed that deletion of S1P2 exclusively in BMDCs promoted tumor growth and angiogenesis. These observations indicate that S1P2 on ECs and BMDCs mediates potent inhibition of tumor angiogenesis, and open the possibility of a novel anti-angiogenic strategy to target S1P2.