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Targetting Cysteinyl Leukotriene 2 Receptor as a Therapeutic Target for Tumor Growth and Metastasis: A New Function for an Old Receptor
Author(s) -
Teegala Lakshminarayan Reddy,
Duah Ernest,
Kondeti Vinay,
AlAzzam Nosayba Zakariya,
Adapala Ravi,
Ghebreigziabher Samrawit,
Thodeti Charles,
Paruchuri Sailaja
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.946.9
Subject(s) - angiogenesis , metastasis , tumor microenvironment , cancer research , tumor progression , inflammation , cancer , lewis lung carcinoma , receptor , biology , chemistry , medicine , immunology
Excessive or insufficient angiogenesis can lead to number of diseases including atherosclerosis, diabetic retinopathy, age‐related macular degeneration and cancer. Although long‐standing inflammation secondary to chronic infection or irritation mediated by immune cells has been implicated in cancer progression, the contribution of endothelial cells (EC) in the generation of inflammatory mediators and their effects on angiogenesis is relatively unknown. One of the pro‐inflammatory mediators produced by EC are cysteinyl leukotrienes (Cys‐LTs: LTC 4 , LTD 4 and LTE 4 ), and they mediate their effects through two main receptors, CysLT 1 R and CysLT 2 R. Cys‐LTs have been shown to be involved in several human cancers including breast cancer and melanoma. Tumor microenvironment comprises numerous signaling molecules and pathways that influence angiogenic response leading to increased and aberrant vascularization. Further, angiogenesis is required for the supply of nutrients and oxygen for tumor growth and also serves as a route of tumor cells metastasis. Therefore, we investigated the role of CysLTR in angiogenesis, tumor progression and metastasis, using mice lacking CysLT 1 R (CysLT 1 RKO) and CysLT 2 R (CysLT 2 RKO). We observed enhanced CysLT 2 R expression, and not CysLT 1 R in wild type (WT) tumors and tumor growth as well as angiogenesis were significantly decreased in CysLT 2 RKO mice compared to WT and CysLT 1 RKO mice in Lewis lung carcinoma (LLC) tumor model. Further, though few in number, tumor vessels in CysLT 2 RKO mice showed intact pericyte coverage and reduced permeability with simultaneous reduction in tumor cell metastasis to the lung. Furthermore, we found that activation of CysLT 2 R, but not CysLT 1 R increased EC contraction leading to junctional destabilization and permeability in vitro. Importantly, our results show that CysLT 2 R activates Rho kinase and inhibition of Rho kinase significantly attenuated CysLT 2 R‐induced EC contraction and permeability. Further, our preliminary results revealed that pericytes express CysLT 2 R and display calcium influx in response to LTD 4 . Taken together, our results suggest that CysLT 2 R promotes leaky blood vessel formation, enhancing tumor growth and metastasis to the lung. Blocking CysLT 2 R could offer novel CysLT 2 R‐targeted, therapeutic candidates for the treatment of cancer and other angiogenic disorders. Support or Funding Information James Foght Professorship Support, AHA GIA 15GRNT 25670004