Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
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DOI：
10.1038/onc.2015.83
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发表时间：
2016-01-21
期刊：
影响因子：
8
通讯作者：
Thodeti CK
中科院分区：
文献类型：
--
作者：
Adapala RK;Thoppil RJ;Ghosh K;Cappelli HC;Dudley AC;Paruchuri S;Keshamouni V;Klagsbrun M;Meszaros JG;Chilian WM;Ingber DE;Thodeti CK
肿瘤血管的特征在于异常形态和高渗透性，这两者共同导致化疗剂的低效递送。虽然VEGF已被确定为肿瘤血管生成的关键调节因子，但机械信号传导在肿瘤血管系统或肿瘤内皮细胞（TEC）功能调节中的作用尚不清楚。在这里，我们表明，机械敏感性离子通道TRPV4调节肿瘤血管生成和肿瘤血管成熟，通过调节TEC机械敏感性。我们发现TEC表现出TRPV4表达和功能降低，这与TEC对ECM刚度的异常机械敏感性、增加的迁移和异常血管生成相关。此外，同源肿瘤实验揭示，TRPV4的缺乏诱导增加的血管密度、血管直径和减少的周细胞覆盖，导致TRPV4 KO小鼠中增强的肿瘤生长。重要的是，TRPV4的过表达或药理学激活通过调节Rho活性在体外恢复异常TEC机械敏感性、迁移和正常化异常血管生成。最后，TRPV4的小分子激活剂GSK1016790A与抗癌药物顺铂组合，通过诱导血管成熟显著降低WT小鼠中的肿瘤生长。我们的研究结果表明TRPV4通道是肿瘤血管生成的关键调节因子，并代表了抗血管生成和血管正常化治疗的新靶点。
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.