血管生成
血管内皮生长因子
癌症研究
成纤维细胞生长因子
生长因子
血管内皮生长因子A
生物
内皮干细胞
人脐静脉内皮细胞
细胞外
脐静脉
贝伐单抗
血管生成抑制剂
细胞生物学
受体
体外
生物化学
血管内皮生长因子受体
化疗
遗传学
作者
Jiao Li,Xue Liu,Shizhu Zang,Jiasheng Zhou,Fuyin Zhang,Bo Sun,Dongyuan Qi,Xiaojie Li,Jing Kong,Dong‐Yan Jin,Xuesong Yang,Yong Luo,Yao Lu,Bingcheng Lin,Weidong Niu,Tingjiao Liu
标识
DOI:10.1016/j.canlet.2020.08.030
摘要
The blood vessel growth inhibitor bevacizumab targets vascular endothelial growth factor (VEGF), a crucial regulator of angiogenesis. Recently, small extracellular vesicles (sEVs) have been demonstrated to be important vehicles in the transport of growth factors to target cells. In this study, we isolated primary carcinoma-associated fibroblasts (CAFs) from four human oral squamous cell carcinoma (OSCC) specimens. Compared with other non-extracellular vesicle components, CAF-derived sEVs were found to be the main regulators of angiogenesis. The ability of CAF sEVs to activate VEGF receptor 2 (VEGFR2) signaling in human umbilical vein endothelial cells (HUVEC) was dependent on the association between sEVs and VEGF. In addition, sEV-bound VEGF secreted by CAFs further activated VEGFR2 signaling in HUVEC in a bevacizumab-resistant manner. VEGF was found to interact with heparan sulfate proteoglycans on the CAF sEV surface and could be released by heparinase I/III. The bioactivity of the dissociated VEGF was retained in vitro and in vivo and could be neutralized by bevacizumab. These findings suggest that the combined use of heparinase and bevacizumab might inhibit angiogenesis in patients with high levels of sEV-bound VEGF.
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