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Supplementary Figure 4 from S1P2, the G Protein–Coupled Receptor for Sphingosine-1-Phosphate, Negatively Regulates Tumor Angiogenesis and Tumor Growth In vivo in Mice

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posted on 2023-03-30, 19:52 authored by Wa Du, Noriko Takuwa, Kazuaki Yoshioka, Yasuo Okamoto, Koichi Gonda, Kazushi Sugihara, Akiyoshi Fukamizu, Masahide Asano, Yoh Takuwa
Supplementary Figure 4 from S1P2, the G Protein–Coupled Receptor for Sphingosine-1-Phosphate, Negatively Regulates Tumor Angiogenesis and Tumor Growth In vivo in Mice

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ARTICLE ABSTRACT

Sphingosine-1-phosphate (S1P) has been implicated in tumor angiogenesis by acting through the Gi-coupled chemotactic receptor S1P1. Here, we report that the distinct receptor S1P2 is responsible for mediating the G12/13/Rho-dependent inhibitory effects of S1P on Akt, Rac, and cell migration, thereby negatively regulating tumor angiogenesis and tumor growth. By using S1P2LacZ/+ mice, we found that S1P2 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 S1P2-deficient (S1P2−/−) mice displayed accelerated tumor growth and angiogenesis with enhanced association of vascular smooth muscle cells and pericytes. S1P2−/− ECs exhibited enhanced Rac activity, Akt phosphorylation, cell migration, proliferation, and tube formation in vitro. Coinjection of S1P2−/− ECs and tumor cells into wild-type mice also produced a relative enhancement of tumor growth and angiogenesis in vivo. S1P2−/− mice were also more efficient at recruiting CD11b-positive BMDCs into tumors compared with wild-type siblings. Bone marrow chimera experiments revealed that S1P2 acted in BMDCs to promote tumor growth and angiogenesis. Our results indicate that, in contrast to endothelial S1P1, which stimulates tumor angiogenesis, S1P2 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

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