Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis.

Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis.

Duah Ernest; Teegala Lakshminarayan Reddy; Kondeti Vinay; Adapala Ravi K; Keshamouni Venkateshwar G; Kanaoka Yoshihide; Austen K Frank; Thodeti Charles K; Paruchuri Sailaja

Proceedings of the National Academy of Sciences of the United States of America

2019

2019-01

Cysteinyl leukotrienes (cys-LTs) are proinflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (ECs) and in Matrigel implants in WT mice and enhances EC contraction and permeability via the Rho-dependent myosin light chain 2 and vascular endothelial (VE)-cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyperpermeability, we hypothesized that CysLT2R, via its actions on the endothelium, might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R-null mice (Cysltr2 (-/-)) compared with WT and CysLT1R-null mice (Cysltr1 (-/-)). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared with CysLT1R. Further, the tumor vasculature in Cysltr2 (-/-) recipients exhibited significantly improved integrity, as revealed by increased pericyte coverage and decreased leakage of i.v.-administered Texas Red-conjugated dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage, and metastases in WT mice, highlighting CysLT2R as a VEGF-independent regulator of the vasculature promoting risk of metastasis. Thus, both genetic and pharmacological findings establish CysLT2R as a gateway for angiogenesis and EC dysregulation in vitro and ex vivo and in an in vivo model with a mouse tumor. Our data suggest CysLT2R as a possible target for intervention.

*angiogenesis; *cysteinyl leukotriene receptors; *endothelial cells; *metastasis; *tumor growth; Male; Animals; Mice; Gene Knockout Techniques; Lung Neoplasms/drug therapy; Neoplasm Transplantation; Neoplasms; Receptors; Inbred C57BL; Neovascularization; Experimental; Capillary Permeability/drug effects; Cyclohexanecarboxylic Acids/pharmacology; Endothelial Cells/*drug effects; Leukotriene Antagonists/pharmacology; Neoplasm Metastasis/drug therapy; Phthalic Acids/pharmacology; Leukotriene/drug effects/*metabolism; Pathologic/*chemically induced/drug therapy

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