第85回 日本生理学会 2008年3月25日〜27日(東京


S1P2 receptor (S1P2R) negatively regulates tumor angiogenesis and tumor development in vivo


W. Du, N. Takuwa, K. Yoshioka, F. Wang, C. Nagakura, E. Kaneko and Y. Takuwa



ABSTRACT

Background Plasma-derived lipid mediator sphingosine-1-phosphate (S1P) acts via the G protein-coupled S1P receptor family to regulate a variety of physiological and pathological responses. S1P1 receptor mediates endothelial cell migration and vascular maturation, promoting vascular integrity. We have previously shown that S1P2R is distinct from S1P1R in that it negatively regulates cell migration and endothelial capillary tube formation in vitro. In the present study we investigated the role of host cell S1P2R in tumor angiogenesis and development by comparing S1P2 knock out (KO) and their wild type (WT) littermate mice.
Methods and Results Lewis lung carcinoma cells and B16BL6 melanoma cells were subcutaneously injected to S1P2KO and WT mice and allowed to grow for 3 weeks. In both types of tumor cells, tumor development was significantly greater in S1P2KO as compared with WT. Tumors in KO mice displayed increased numbers of blood vessels which were associated with much higher numbers of desmin-positive mural cells, and marked upregulation of angiogenic factors including VEGF, Notch signaling mediator Delta-like ligand 4 and TGFβ1.
Conclusions These results indicate that S1P2R negatively regulates tumor angiogenesis in vivo, with inhibition of angiogenic gene expression and mural cell recruitment, resulting in inhibition of tumor growth. S1P2R-selective agonist would be a promising anti-tumor therapeutic agent.