Endothelial sphingosine 1-phosphate receptors promote vascular normalization to influence tumor growth and metastasis

Abstract Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1pr1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy. Significance Endothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.