Small extracellular vesicle-bound vascular endothelial growth factor secreted by carcinoma-associated fibroblasts promotes angiogenesis in a bevacizumab-resistant manner. (1st November 2020)

• Record Type: Journal Article
• Authors: Li, Jiao; Liu, Xue; Zang, Shizhu; Zhou, Jiasheng; Zhang, Fuyin; Sun, Bo; Qi, Dongyuan; Li, Xiaojie; Kong, Jing; Jin, Dong; Yang, Xuesong; Luo, Yong; Lu, Yao; Lin, Bingcheng; Niu, Weidong; Liu, Tingjiao
• Is Part Of: Cancer letters. Volume 492(2020)
• Page Start: 71
• Page End: 83
• Publication Date: 2020-11-01
• Subjects: EV-Bound VEGF -- Extracellular vesicles -- Bevacizumab -- Heparinase -- Carcinoma-associated fibroblast; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.08.030
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: SEV-bound VEGF secreted by CAF is not neutralized by bevacizumab. CAF sEVs activate prolonged VEGFR2-AKT-ERK signaling. Heparinase releases sEV-bound VEGF. VEGF released from CAF sEVs reversed cell sensitivity to bevacizumab.