Description
Transient receptor potential vanilloid 4 (TRPV4) is a ubiquitously expressed polymodally activated ion channel. TRPV4 has been implicated in tumor progression; however, the cell-specific role of TRPV4 in tumor growth, angiogenesis, and metastasis is unknown. Here, we generated endothelial-specific TRPV4 knockout (TRPV4ECKO) mice by crossing TRPV4lox/lox mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4ECKO mice compared to TRPV4lox/lox mice. Multiphoton microscopy, dextran leakage, and immunohistochemical analysis revealed increased tumor angiogenesis and metastasis that were correlated with aberrant leaky vessels (increased width and reduced pericyte and VE-cadherin coverage). Mechanistically, increases in VEGFR2, p-ERK, and MMP-9 expression and DQ gelatinase activity were observed in the TRPV4ECKO mouse tumors. Our results demonstrated that endothelial TRPV4 is a critical modulator of vascular integrity and tumor angiogenesis and that deletion of TRPV4 promotes tumor angiogenesis, growth, and metastasis.
Subject
TRPV4 is a polymodal cation channel activated by hypotonicity, temperature, shear stress, arachidonic acid, epoxyeicosatrienoic acid (EET), matrix stiffness, and mechanical stretch in various cell types [1,2,3,4,5,6,7,8,9]. Recently, TRPV4 has been implicated in the growth and progression of breast, gastric, colon, and melanoma cancers [10,11,12,13,14,15]. In contrast to these findings, Peters et al. demonstrated that activation of TRPV4 induced oncosis and apoptosis of breast cancer cells in vitro and reduced tumor growth in vivo [16]. These findings suggest that either activation or inhibition of TRPV4 in tumor cells can differentially regulate tumor growth and metastasis of different tumors.