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Mol Cancer. 2015 Jul 29;14:140. doi: 10.1186/s12943-015-0418-x.

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

Author information

1
Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China.
2
Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
3
Drug Discovery Research Center, Sichuan Medical University, Luzhou, Sichuan, People's Republic of China. wuji@missouri.edu.
4
Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA. wuji@missouri.edu.

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.

CONCLUSION:

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.

PMID:
26215730
PMCID:
PMC4517418
DOI:
10.1186/s12943-015-0418-x
[Indexed for MEDLINE]
Free PMC Article

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