PT  - JOURNAL ARTICLE
AU  - Xiaoling Zhang
AU  - Yan Zhang
AU  - Yanan Jia
AU  - Tingting Qin
AU  - Cuicui Zhang
AU  - Yueya Li
AU  - Chengmou Huang
AU  - Zhujun Liu
AU  - Jing Wang
AU  - Kai Li
TI  - Bevacizumab promotes active biological behaviors of human umbilical vein endothelial cells by activating TGFβ1 pathways <strong>via</strong> off-VEGF signaling
AID  - 10.20892/j.issn.2095-3941.2019.0215
DP  - 2020 May 15
TA  - Cancer Biology and Medicine
PG  - 418--432
VI  - 17
IP  - 2
4099  - http://www.cancerbiomed.org/content/17/2/418.short
4100  - http://www.cancerbiomed.org/content/17/2/418.full
SO  - Cancer Biol Med2020 May 15; 17
AB  - Objective: Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF) with clear clinical benefits. However, overall survival of some cancer types remains low owing to resistance to bevacizumab therapy. While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor (HIF), less attention has been paid to the potential involvement of endothelial cells (ECs) in vasculature activated by anti-angiogenic drugs.Methods: Human umbilical vein ECs (HUVECs), bEnd.3 cells, and mouse retinal microvascular ECs (MRMECs) were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors, such as migration and tube formation, examined. Regulatory effects on TGFβ1 and CD105 (endoglin) were established via determination of protein and mRNA levels. We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib.Results: Bevacizumab upregulated TGFβ1 as well as CD105, a component of the TGFβ receptor complex and an angiogenesis promoter. Elevated CD105 induced activation of Smad1/5, the inflammatory pathway and endothelial–mesenchymal transition. The migration ability of HUVECs was enhanced by bevacizumab under hypoxia. Upregulation of CD105 was abrogated by anlotinib, which targets multiple receptor tyrosine kinases including VEGFR2/3, FGFR1-4, PDGFRα/β, C-Kit, and RET.Conclusions: Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβ1 pathway and upregulation of CD105 expression. Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.