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Shedding of bevacizumab in tumour cells-derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma

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Title: Shedding of bevacizumab in tumour cells-derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma
Authors: Simon, T
Pinioti, S
Schellenberger, P
Rajeeve, V
Wendler, F
Cutillas, PR
King, A
Stebbing, J
Giamas, G
Item Type: Journal Article
Abstract: Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity.
Issue Date: 31-Aug-2018
Date of Acceptance: 15-Aug-2018
URI: http://hdl.handle.net/10044/1/62586
DOI: https://dx.doi.org/10.1186/s12943-018-0878-x
ISSN: 1476-4598
Publisher: BioMed Central
Journal / Book Title: Molecular Cancer
Volume: 17
Issue: 1
Copyright Statement: © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Extracellular vesicles
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Article Number: 132
Online Publication Date: 2018-08-31
Appears in Collections:Department of Surgery and Cancer