S1P2, the G Protein–Coupled Receptor for Sphingosine-1-Phosphate, Negatively Regulates Tumor Angiogenesis and Tumor Growth In vivo in Mice

Abstract

Sphingosine-1-phosphate (S1P) has been implicated in tumor angiogenesis by acting through the G i -coupled chemotactic receptor S1P 1 . Here, we report that the distinct receptor S1P 2 is responsible for mediating the G 12/13 /Rho-dependent inhibitory effects of S1P on Akt, Rac, and cell migration, thereby negatively regulating tumor angiogenesis and tumor growth. By using S1P 2 LacZ/+ mice, we found that S1P 2 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 2 -deficient (S1P 2 −/− ) mice displayed accelerated tumor growth and angiogenesis with enhanced association of vascular smooth muscle cells and pericytes. S1P 2 −/− ECs exhibited enhanced Rac activity, Akt phosphorylation, cell migration, proliferation, and tube formation in vitro. Coinjection of S1P 2 −/− ECs and tumor cells into wild-type mice also produced a relative enhancement of tumor growth and angiogenesis in vivo. S1P 2 −/− mice were also more efficient at recruiting CD11b-positive BMDCs into tumors compared with wild-type siblings. Bone marrow chimera experiments revealed that S1P 2 acted in BMDCs to promote tumor growth and angiogenesis. Our results indicate that, in contrast to endothelial S1P 1 , which stimulates tumor angiogenesis, S1P 2 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. ©2010 AACR.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…The high S1PR1 expression in glioblastoma patients was positively associated with favorable survival 42. However, S1PR2 signaling negatively regulates tumor angiogenesis and tumor growth in vivo 43. S1PR2 is also involved in the reduction of platelet‐derived growth factor mediated‐cell motility and proliferation 44.…”

Sphingosine‐1‐phosphate signaling in physiology and diseases

“…In normal tissues of S1P 2 +/LacZ mice, LacZ activity is detected in various sizes of 9 blood vessels in a variety of organs, which include lung, brain, skeletal muscle, kidney, and liver [31]. Vascular cells are the major cell types that express S1P 2 in many organs.…”

“…Thus, different from S1P 1 , S1P 2 is a negative regulator of angiogenesis. S1P 2 deletion enhances angiogenesis in implanted tumors with accelerated tumor growth [31]. In tumors, S1P 2 is expressed in ECs and mural cells in tumor vessels.…”

“…In addition to ECs, S1P 2 is also expressed in CD11b + positive bone marrow-derived cells (BMDCs) in the tumor stroma [31]. Myeloid cells including CD11b + cells participate in tumor angiogenesis through multiple mechanisms [36].…”

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

“…Importantly, anaphylactic shock has been shown to depend on eNOS activation mediated by endothelial G q/11 and phosphatidylinositol 3-kinase (PI3K)-Akt. 26,27 We recently found that endogenous S1P 2 mediates inhibition of Akt in EC, 10 unlike S1P 1 which stimulates eNOS via Akt. 28 These observations raise the possibility that S1P 2 might suppress eNOS through inhibition of Akt, exerting a Cui 8 rescue effect on vascular hyperpermeability.…”