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

Title

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

Creator

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

Publisher

Oncogene

Date

2016
2016-01

Description

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.

Subject

Animals; Calcium Signaling/genetics; Carcinoma; Cell Line; Cell Proliferation/drug effects; Cisplatin/administration & dosage; Endothelium; Gene Expression Regulation; Humans; Leucine/administration & dosage/analogs & derivatives; Lewis Lung/drug therapy/*genetics/pathology; Mice; Neoplastic/drug effects; Neovascularization; Pathologic/drug therapy/*genetics/pathology; Sulfonamides/administration & dosage; TRPV Cation Channels/agonists/biosynthesis/*genetics; Tumor; Vascular Endothelial Growth Factor A/genetics; Vascular/drug effects/*pathology

Identifier

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

314–322

Issue

3

Volume

35

Citation

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, “Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.,” NEOMED Bibliography Database, accessed April 16, 2021, https://neomed.omeka.net/items/show/3992.

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