Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity.
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.
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.
Kanugula AK; Adapala RK; Jamaiyar A; Lenkey N; Guarino BD; Liedtke W; Yin L; Paruchuri S; Thodeti CK
Angiogenesis
2021
2021-03-03
Journal Article
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1007/s10456-021-09775-9">http://doi.org/10.1007/s10456-021-09775-9</a></td>
</tr></tbody></table>
Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity.
Endothelial cell; Metastasis; Transient receptor potential vanilloid 4; Tumor angiogenesis; Vascular endothelial growth factor receptor 2
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 (TRPV4(ECKO)) mice by crossing TRPV4(lox/lox) mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4(ECKO) mice compared to TRPV4(l)(ox/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 TRPV4(ECKO) 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.
Kanugula AK; Adapala RK; Jamaiyar A; Lenkey N; Guarino BD; Liedtke W; Yin L; Paruchuri S; Thodeti CK
Angiogenesis
2021
2021-03-03
journalArticle
<a href="http://doi.org/10.1007/s10456-021-09775-9" target="_blank" rel="noreferrer noopener">10.1007/s10456-021-09775-9</a>