腫瘍血管新生におけるスフィンゴシンー1 −リン酸受容体S1P2 の役割
Wa Du, 多久和典子, 吉岡和晃, 岡本安雄, Xun Qi, Fei Wang, Hong Cui, Kuntal Biswas, 杉原一
司, 浅野雅秀, 多久和陽
ABSTRACT
Sphingosine-1-phosphate
(S1P) has pleiotropic activities including the regulation
of cell motility, actin cytoskeleton, and cell
proliferation via three major widely expressed G
protein-coupled receptors, S1P1, S1P2 and S1P3. S1P has
been implicated in tumor angiogenesis by acting via a
Gi-coupled chemotactic receptor S1P1 which is
expressed in vascular endothelial cells. Distinctly from
S1P1, S1P2 mediates S1P inhibition of Rac and cell
migration via G12/13 and the Rho pathway. The detailed
expression of S1P2 in vascular cells and its role in tumor
angiogenesis remained unknown. By using S1P2(
LacZ/+)
mice, we
found that S1P2 was expressed in normal blood vessels in
many organs and tumor vessels in both endothelial cells
(ECs) and VSMCs, as well as tumor-associated,
CD11b-positive bone marrow-derived cells (BMDCs). Lewis
lung carcinoma (LLC) and B16BL6 melanoma tumors implanted
in S1P2-deficient (S1P2-/-) mice showed accelerated tumor
growth, stimulated angiogenesis with enhanced association
of vascular mural cells, and increased recruitment of
CD11b-positive BMDCs, compared with tumors in S1P2-/-
siblings. Compared with S1P2+/+ ECs, S1P2-/- ECs showed
enhanced Rac activity, cell migration, proliferation and
tube formation in vitro, and promotion of tumor growth and
angiogenesis in vivo when co-injected with tumor cells into
S1P2+/+ mice. The bone marrow transplantation experiments
showed that deletion of S1P2
exclusively
in BMDCs promoted tumor growth and angiogenesis. These
observations indicate that S1P2
on ECs
and BMDCs mediates potent inhibition of tumor angiogenesis,
and open the possibility of a novel anti-angiogenic
strategy to target S1P2.