Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Harvard University
  • Cornell University

Details

Original languageEnglish (US)
Pages (from-to)3157-3166
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number6
StatusPublished - Feb 11 2020
Peer-reviewedYes

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 paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (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, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1pr1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.

    Research areas

  • Angiogenesis, Cancer, G protein-coupled receptor, Immunotherapy, Sphingosine 1-phosphate

Citation formats

APA

Cartier, A., Leigh, T., Liu, C. H., & Hla, T. (2020). Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy. Proceedings of the National Academy of Sciences of the United States of America, 117(6), 3157-3166. https://doi.org/10.1073/pnas.1906246117

Harvard

Cartier, A, Leigh, T, Liu, CH & Hla, T 2020, 'Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 6, pp. 3157-3166. https://doi.org/10.1073/pnas.1906246117