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

Abstract

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.

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

“…CysLTs are well known for their role in inflammation, particularly in asthma and allergic rhinitis. Recently, however, a role for CysLTs in cancer has emerged [ 9 , 21 ], with a particular focus on their role in vascular permeability and angiogenesis [ 22 ]. In a retrospective analysis, CysLT 1 antagonists, montelukast and zafirlukast, display a dose-dependent chemopreventative effect against 14 different cancers [ 23 ].…”

Is There a Role for Basophils in Cancer?

“…The proangiogenic activities of LTC 4 and LTD 4 were also confirmed in vivo and were found to be mediated by the engagement of CysLT 2 R on blood endothelial cells (BECs). CysLT 2 R deficiency and pharmacologic antagonism reduced tumor growth and the formation of lung metastases in a mouse model of Lewis lung carcinoma (151). These novel findings emphasize the importance of cys-LTs as non-canonical angiogenic factors in cancer.…”

“…These novel findings emphasize the importance of cys-LTs as non-canonical angiogenic factors in cancer. It is possible to speculate that LTC 4 released by circulating basophils can activate CysLT 2 R overexpressed in tumor BECs (151), thus contributing to angiogenesis. It has been suggested that CysLT 2 R might represent a possible pharmacologic target in tumor growth and metastases formation (151).…”

“…Cys-LTs activate three distinct receptors (CysLTRs) CysLT 1 R, CysLT 2 R, and CysLT 3 R ( 148 – 150 ). Recent evidence demonstrates that LTC 4 and LTD 4 were equipotent in forming tubes in the Matrigel in vitro assay of angiogenesis ( 151 ). The proangiogenic activities of LTC 4 and LTD 4 were also confirmed in vivo and were found to be mediated by the engagement of CysLT 2 R on blood endothelial cells (BECs).…”

Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors

“…This study advanced our preclinical knowledge of our novel small molecule CysLT 1 antagonist, 1,4-dihydroxy quininib in CRC. Cysteinyl leukotrienes are bioactive lipids derived from arachidonic acid [33] and through their receptors, CysLTs enhance vascular permeability, promote inflammation and angiogenesis [33,34]. Target profiling demonstrated that similar to the parent compound quininib (Q1), 1,4-dihydroxy quininib is a CysLT 1 antagonist [21,22].…”