title: S1P(2), 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.
authors.affiliation: Department of Physiology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
authors.forename: Wa
authors.initials: W
authors.lastname: Du
authors.forename: Noriko
authors.initials: N
authors.lastname: Takuwa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Gonda
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: D049349:Receptors, Lysosphingolipid