Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma

Molecular Cancer

Research

William P. Fay¹  Rong Li²  Liqun Wang²  Mao Luo²  Yan Yang²  Yongjie Li²  Kai Yan²  Xin Deng²  Ni Chen²  Meiping Ren²  Lamei Xiao²  Jianbo Wu³ 

[1] Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA;Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People’s Republic of China;Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People’s Republic of China;Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA;

关键词: Bevacizumab;    Cancer;    Plasminogen activator inhibitor 1;    VEGF-A;    Venous thromboembolism;   

DOI  :  10.1186/s12943-015-0418-x

 received in 2015-06-01, accepted in 2015-07-20,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAn 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.MethodsInferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.ResultsWe 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.ConclusionCollectively, 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.

【 授权许可】

Unknown   
© Chen et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.