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Activation of mechanosensitive ion channel TRPV4 promotes normalization of tumor vasculature and improves cancer therapy (893.12)
Author(s) -
Thoppil Roslin,
Adapala Ravi Kumar,
Cappelli Holly,
Ghosh Kaustabh,
Dudley Andrew,
Paruchuri Sailaja,
Keshamouni Venkateshwar,
Klagsbrun Michael,
Meszaros J. Gary,
Chilian William,
Ingber Donald,
Thodeti charles
Publication year - 2014
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.28.1_supplement.893.12
Subject(s) - angiogenesis , cancer research , trpv4 , chemistry , neovascularization , tumor microenvironment , medicine , transient receptor potential channel , tumor cells , receptor
The impaired development of tumor vessels, attributed to their highly permeable, tortuous, and hyper‐dilatory properties make it a barrier for the efficient delivery of anti‐cancer agents. Although anti‐VEGF therapies have shown to induce transient normalization of the tumor vasculature and increase the efficacy of cancer drugs, they are met with limited success clinically. Here, we demonstrate that a mechanosenstive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation. Tumor xenograft experiments revealed that, compared to tumors in wild type (WT) mice, those in TRPV4 null mice exhibit greater vascular density and immaturity (increased vessel diameter and reduced pericyte coverage). Endothelial cells derived from the tumor (TEC) showed reduced TRPV4 expression and activity associated with high basal Rho activity as well as aberrant mechanosensitivity and abnormal angiogenesis. Activation of TRPV4 with a small‐molecule activator, GSK1016790A, or TRPV4 overexpression suppressed the endogenously high rho activity, normalized the aberrant capillary formation and abnormal migration exhibited by TEC in vitro. Finally, GSK1016790A in combination with anti‐cancer drug Cisplatin, but not alone, reduced tumor growth in WT mice by normalizing the tumor vessels. Together, these studies demonstrate that TRPV4 channels are critical regulators of tumor angiogenesis, and represent a potential novel therapeutic target for tumor vascular normalization and improving the efficacy of anti‐cancer drugs.