Role of Cysteinyl Leukotriene 2 Receptor in Tumor Angiogenesis, Permeability and Metastasis

Cysteinyl leukotrienes (cys‐LTs) are pro‐inflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT 2 R regulates angiogenesis in isolated mouse endothelial cells (EC) and in Matrigel implants in WT mice, and enhances EC contraction and permeability via Rho‐dependent myosin light chain 2 and VE‐cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyper‐permeability, we hypothesized that CysLT 2 R via its actions on endothelium might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT 2 R null mice ( Cysltr2 −/− ) compared to WT and CysLT 1 R null mice ( Cysltr1 −/− ). In WT recipients of LLC cells, CysLT 2 R expression is significantly increased in the tumor vasculature, compared to CysLT 1 R. Further, tumor vasculature in Cysltr2 −/− recipients exhibited significantly improved integrity as revealed by increased pericyte coverage and decreased leakage of intravenously administered Texas Red‐labeled dextran. Administration of a selective CysLT 2 R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage and metastases in WT mice, highlighting CysLT 2 R as a VEGF‐independent novel regulator of vasculature, promoting risk of metastasis. Thus, both genetic and pharmacologic findings establish CysLT 2 R as a gateway for angiogenesis and endothelial cell dysregulation in vitro and ex vivo and in vivo model with a mouse tumor. Finally, analysis of primary human lung adenocarcinoma data set revealed a strong correlation between poor survival and high CysLT 2 R expression, suggesting CysLT 2 R as a possible target for intervention. Support or Funding Information James Foght Professorship Support, AHA GIA 15GRNT 25670004 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .