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

摘要

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 TGFpi and CD 105(endoglin)were established via determination o f 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 TGFpi as well as CD 105,a component o f the TGFP receptor complex and an angiogenesis promoter.Elevated CD 105 induced activation of Sm adl/5,the inflammatory pathway and endothelial-mesenchymal transition.The migration ability of HUVECs was enhanced by bevacizumab under hypoxia.Upregulation o f CD 105 was abrogated by anlotinib,which targets multiple receptor tyrosine kinases including VEGFR2/3,FGFR1-4,PD G FRα/β,C-Kit,and RET.Conclusions:Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβi pathway and upregulation of CD105 expression.Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.