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Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma
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 antibo...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517418/ https://www.ncbi.nlm.nih.gov/pubmed/26215730 http://dx.doi.org/10.1186/s12943-015-0418-x |
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author | Chen, Ni Ren, Meiping Li, Rong Deng, Xin Li, Yongjie Yan, Kai Xiao, Lamei Yang, Yan Wang, Liqun Luo, Mao Fay, William P. Wu, Jianbo |
author_facet | Chen, Ni Ren, Meiping Li, Rong Deng, Xin Li, Yongjie Yan, Kai Xiao, Lamei Yang, Yan Wang, Liqun Luo, Mao Fay, William P. Wu, Jianbo |
author_sort | Chen, Ni |
collection | PubMed |
description | 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 FeCl(3)-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. |
format | Online Article Text |
id | pubmed-4517418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45174182015-07-29 Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma Chen, Ni Ren, Meiping Li, Rong Deng, Xin Li, Yongjie Yan, Kai Xiao, Lamei Yang, Yan Wang, Liqun Luo, Mao Fay, William P. Wu, Jianbo Mol Cancer Research 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 FeCl(3)-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. BioMed Central 2015-07-29 /pmc/articles/PMC4517418/ /pubmed/26215730 http://dx.doi.org/10.1186/s12943-015-0418-x Text en © 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. |
spellingShingle | Research Chen, Ni Ren, Meiping Li, Rong Deng, Xin Li, Yongjie Yan, Kai Xiao, Lamei Yang, Yan Wang, Liqun Luo, Mao Fay, William P. Wu, Jianbo Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title | Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title_full | Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title_fullStr | Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title_full_unstemmed | Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title_short | Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma |
title_sort | bevacizumab promotes venous thromboembolism through the induction of pai-1 in a mouse xenograft model of human lung carcinoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517418/ https://www.ncbi.nlm.nih.gov/pubmed/26215730 http://dx.doi.org/10.1186/s12943-015-0418-x |
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