Data from S1P<sub>2</sub>, the G Protein–Coupled Receptor for Sphingosine-1-Phosphate, Negatively Regulates Tumor Angiogenesis and Tumor Growth <i>In vivo</i> in Mice

Abstract

<div>Abstract<p>Sphingosine-1-phosphate (S1P) has been implicated in tumor angiogenesis by acting through the G<sub>i</sub>-coupled chemotactic receptor S1P<sub>1</sub>. Here, we report that the distinct receptor S1P<sub>2</sub> is responsible for mediating the G<sub>12/13</sub>/Rho-dependent inhibitory effects of S1P on Akt, Rac, and cell migration, thereby negatively regulating tumor angiogenesis and tumor growth. By using <i>S1P</i><sub>2</sub><sup><i>LacZ</i>/+</sup> mice, we found that S1P<sub>2</sub> was expressed in both tumor and normal blood vessels in many organs, in both endothelial cells (EC) and vascular smooth muscle cells, as well as in tumor-associated, CD11b-positive bone marrow–derived cells (BMDC). Lewis lung carcinoma or B16 melanoma cells implanted in S1P<sub>2</sub>-deficient (<i>S1P</i><sub>2</sub><sup>−/−</sup>) mice displayed accelerated tumor growth and angiogenesis with enhanced association of vascular smooth muscle cells and pericytes. <i>S1P</i><sub>2</sub><sup>−/−</sup> ECs exhibited enhanced Rac activity, Akt phosphorylation, cell migration, proliferation, and tube formation <i>in vitro</i>. Coinjection of <i>S1P</i><sub>2</sub><sup>−/−</sup> ECs and tumor cells into wild-type mice also produced a relative enhancement of tumor growth and angiogenesis <i>in vivo. S1P</i><sub>2</sub><sup>−/−</sup> mice were also more efficient at recruiting CD11b-positive BMDCs into tumors compared with wild-type siblings. Bone marrow chimera experiments revealed that S1P<sub>2</sub> acted in BMDCs to promote tumor growth and angiogenesis. Our results indicate that, in contrast to endothelial S1P<sub>1</sub>, which stimulates tumor angiogenesis, S1P<sub>2</sub> on ECs and BMDCs mediates a potent inhibition of tumor angiogenesis, suggesting a novel therapeutic tactic for anticancer treatment. Cancer Res; 70(2); 772–81</p></div>