Bevacizumab promotes active biological behaviors of human umbilical vein endothelial cells by activating TGFβ1 pathways via off-VEGF signaling

Xiaoling Zhang, Yan Zhang, Yanan Jia, et al.

Abstract


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 paidto 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 withbevacizumab 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 furtherinvestigated 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 angiogenesispromoter. Elevated CD105 induced activation of Smad1/5, the inflammatory pathway and endothelial–mesenchymal transition. Themigration 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 andupregulation of CD105 expression. Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.

Cite this article as: Zhang X, Zhang Y, Jia Y, Qin T, Zhang C, Li Y, et al.Bevacizumab promotes active biological behaviors of human umbilical veinendothelial cells by activating TGFβ1 pathways via off-VEGF signaling. CancerBiol Med. 2020; 17: 418-432. doi: 10.20892/j.issn.2095-3941.2019.0215


Keywords


HUVEC; CD105; bevacizumab; anlotinib; TGFβ

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