title: Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma.
abstract: BACKGROUND
  An increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.
  
  
  METHODS
  Inferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.
  
  
  RESULTS
  We found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab's prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis.
  
  
  CONCLUSIONS
  Collectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Meiping
authors.initials: M
authors.lastname: Ren
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Yan
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Lamei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
authors.forename: Mao
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
authors.affiliation: Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China. wuji@missouri.edu.|Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA. wuji@missouri.edu.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D054556:Venous Thromboembolism / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab