Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity.

Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity.

Kanugula AK; Adapala RK; Jamaiyar A; Lenkey N; Guarino BD; Liedtke W; Yin L; Paruchuri S; Thodeti CK

Angiogenesis

2021

2021-03-03

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.

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.

Journal Article

NEOMED College of Medicine

Department of Integrative Medical Sciences

Jan to Aug list 2021