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Endothelial TRPV4 channel deletion promotes tumor growth and metastasis
Author(s) -
Kanugula Anantha Koteswararao,
Adapala Ravi K,
Jamaiyar Anurag K,
Lenkey Nina,
Yin Liya,
Chilian William M,
Paruchuri Sailaja,
Thodeti Charles K
Publication year - 2019
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.2019.33.1_supplement.517.4
Subject(s) - angiogenesis , trpv4 , lewis lung carcinoma , cd31 , cancer research , metastasis , chemistry , transient receptor potential channel , biology , medicine , receptor , cancer , biochemistry
Ion channels have been implicated in tumor growth and metastasis and are considered as one of the promising therapeutic targets. Previously, we have shown that transient receptor potential vanilloid 4 (TRPV4) ion channel is a mechanosensor in endothelial cells (EC) which is downregulated in tumor endothelial cells (TEC). TEC exhibit high basal Rho activity, abnormal migration and angiogenesis in vitro. Mechanistically, we found that TRPV4 regulates EC migration and angiogenesis by integrating mechanical (Rho) and soluble (VEGF) signaling. Importantly, we found that tumor implantation in global TRPV4KO mice resulted in enhanced tumor growth, angiogenesis and lung metastasis compared to wild type mice suggesting that TRPV4 in endothelium negatively regulates tumor angiogenesis. However, the specific role of endothelial TRPV4 in tumor growth, angiogenesis and metastasis is not known. To determine this, we have generated endothelial specific TRPV4KO (TRPV4 ECKO ) mice by crossing TRPV4 lox/lox mice with Tie2‐Cre mice. By employing syngeneic Lewis lung carcinoma tumor model, we found that deletion of endothelial TRPV4 enhanced tumor growth in TRPV4 ECKO mice compared to TRPV4 lox/lox mice. Multiphoton microscopic analysis of tumor sections infused with Alexa‐Fluor isolectin‐B4 revealed tortuous tumor vasculature in TRPV4 ECKO mice compared to TRPV4 lox/lox mice. Further, we found that these vessels show reduced pericyte coverage with concomitant leakiness as evidenced by colocalization of CD31/α‐SMA and dextran leakage, respectively. Western blot analysis revealed increased tyrosine phosphorylation of VEGFR2 at Y1175 (p‐VEGFR2‐Y 1175 ) in tumors from TRPV4 ECKO mice compared to TRPV4 lox/lox . Finally, we found increased metastasis of tumor cells to the lung in TRPV4 ECKO mice. Our results thus confirm that endothelial TRPV4 is a negative regulator of tumor angiogenesis and metastasis and identifies TRPV4 is a novel VEGF‐independent target for tumor angiogenesis and metastasis or vascular normalization. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .