Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the re...

Full description

Saved in:

Bibliographic Details
Published in:	Oncogene Vol. 35; no. 3; pp. 314 - 322
Main Authors:	Adapala, R K, Thoppil, R J, Ghosh, K, Cappelli, H C, Dudley, A C, Paruchuri, S, Keshamouni, V, Klagsbrun, M, Meszaros, J G, Chilian, W M, Ingber, D E, Thodeti, C K
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 21-01-2016 Nature Publishing Group
Subjects:	13/1 13/109 631/67/2328 82/29 96/63 Analysis Angiogenesis Animals Apoptosis Calcium Signaling - genetics Cancer Carcinoma, Lewis Lung - drug therapy Carcinoma, Lewis Lung - genetics Carcinoma, Lewis Lung - pathology Care and treatment Cell Biology Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy Cisplatin - administration & dosage Endothelium, Vascular - drug effects Endothelium, Vascular - pathology Gene Expression Regulation, Neoplastic - drug effects Health aspects Human Genetics Humans Influence Internal Medicine Leucine - administration & dosage Leucine - analogs & derivatives Medicine Medicine & Public Health Mice Neovascularization Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Oncology original-article Protein expression Signal transduction Sulfonamides - administration & dosage TRPV Cation Channels - agonists TRPV Cation Channels - biosynthesis TRPV Cation Channels - genetics Vascular endothelial growth factor Vascular Endothelial Growth Factor A - genetics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 contributed equally to this work.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2015.83