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CysLT2R is a novel therapeutic target for tumor angiogenesis, growth and metastasis
Author(s) -
Teegala Lakshminarayan Reddy,
Duah Ernest,
Kondeti Vinay,
Adapala Ravi,
Thodeti Charles,
Paruchuri Sailaja
Publication year - 2018
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.2018.32.1_supplement.540.4
Subject(s) - angiogenesis , metastasis , cancer research , lewis lung carcinoma , tumor microenvironment , inflammation , tumor progression , cancer , receptor , in vivo , medicine , biology , immunology , microbiology and biotechnology
Angiogenesis plays a vital role in numerous diseases including cancer, atherosclerosis, diabetic retinopathy and age‐related macular degeneration. Although chronic inflammation mediated by immune cells has been known to play a role in neoplastic transformation, there exists limited information on how inflammatory mediators can cause endothelial dysfunction and their role in promoting angiogenesis. Cysteinyl leukotrienes (Cys‐LTs: LTC 4 , LTD 4 and LTE 4 ) are pro‐inflammatory mediators derived from arachidonic acid and signal through two well characterized receptors, CysLT 1 R and CysLT 2 R. Cys‐LTs have been shown to be involved in several human cancers including breast and melanoma. However, the receptors involved and the mechanism of action still remains elusive. We have recently shown that LTD 4 can enhance endothelial cell (EC) contraction and permeability via CysLT 2 R in a Rho‐dependent pathway. Here, we present another seminal observation that LTD 4 can enhance angiogenesis in vitro and in vivo via CysLT 2 R. Since enhanced angiogenesis is required for solid tumor growth, we investigated the role of CysLTR in tumor 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 but not CysLT 1 R in wild type (WT) tumors, in line with the involvement of CysLT 2 R in endothelial dysfunction. Further, tumor growth and angiogenesis were significantly decreased in CysLT 2 RKO mice compared to WT and CysLT 1 RKO mice in subcutaneous Lewis lung carcinoma (LLC) tumor model. Furthermore, though few in number, tumor vessels in CysLT 2 RKO mice exhibited intact pericyte coverage and reduced permeability with simultaneous reduction in tumor cell metastasis to the lung. Finally, blocking CysLT 2 R using a specific CysLT 2 R antagonist BaycysLT2 recapitulated the results obtained with CysLT2RKO mice. Our results suggest that CysLT 2 R promotes tumor angiogenesis and growth as well as metastasis to the lung by disrupting vascular integrity and targeting CysLT 2 R could offer novel VEGF‐independent therapeutic strategy for the treatment of cancer and other angiogenic disorders. Support or Funding Information James Foght Professorship Support, AHA GIA 15GRNT 25670004 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .