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

Abstract

Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF 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 TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM 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 KO 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 anti-cancer drug Cisplatin, significantly reduced tumor growth in WT 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.

Mechanosensitive transient receptor potential vanilloid 4 regulates Dermatophagoides farinae–induced airway remodeling via 2 distinct pathways modulating matrix synthesis and degradation

“…NHLFs were transfected with TRPV‐enhanced green fluorescent protein (EGFP) (2 μg) (22) or EGFP (Thermo Fisher Scientific) alone using siLentFect transfection reagent according to manufacturer instructions. Post‐transfection, cells were preincubated with 50 μM PI3K inhibitor (LY) for 30 min and stimulated with TGF‐β1 (2 ng/ml).…”

Targeting calcium signaling in cancer therapy

“…It is at least 300-fold more potent than the commonly used TRPV4 activator 4 α -PDD 142 . TRPV4 is able to regulate tumor angiogenesis and vessel maturation, thus GSK1016790A has been proposed to be used together with other anticancer drugs, such as cisplatin, to improve tumor penetration for more effective cancer therapy 98 . By mimicking the C-terminus of soricidin, two TRPV6 inhibitors, the SOR-C13 and SOR-C27 bind TRPV6 with high affinity in ovarian cancer cells.…”

The Mechanosensitive Ion Channel TRPV4 is a Regulator of Lung Development and Pulmonary Vasculature Stabilization

“…This demonstrates that TRPV4 activity is essential for stabilization of the PV during lung development. Whereas this is a completely novel finding in lung development, a similar role of TRPV4 has been shown in stabilizing vessels in tumors and after stroke 2,13,60 , suggesting that TRVP4 may be a broad regulator of vessel behavior in tissues undergoing rapid angiogenesis. Importantly, through use of an ex vivo model, these studies have demonstrated that TRPV4 regulates multiple tissue compartments in an intact and growing organ.…”

“…Membranes were blocked with 5% milk in Tris-buffered saline with 0.1% Tween 20 and probed with anti-TRPV4 (Alomone) and with anti-ß-actin (Cell Signaling) as a loading control. Appropriate HRP-conjugated secondary antibodies were used and the membrane developed with Super Signal Femto ECL (ThermoFisher Scientific) and imaged with a ChemiDoc-IT 2 bioimaging system (UVP).…”