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

  • Simon, Thomas1
  • Pinioti, Sotiria1, 2
  • Schellenberger, Pascale1
  • Rajeeve, Vinothini3
  • Wendler, Franz1
  • Cutillas, Pedro R.3
  • King, Alice1
  • Stebbing, Justin4
  • Giamas, Georgios1
  • 1 University of Sussex, School of Life Sciences, Department of Biochemistry and Biomedicine, Brighton, BN1 9QG, UK , Brighton (United Kingdom)
  • 2 Present address: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium , Leuven (Belgium)
  • 3 Queen Mary University of London, Cell Signalling & Proteomics Group, Centre for HaematoOncology, Barts Cancer Institute, London, UK , London (United Kingdom)
  • 4 Imperial College London, Division of Cancer, Department of Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK , London (United Kingdom)
Published Article
Molecular Cancer
Springer (Biomed Central Ltd.)
Publication Date
Aug 31, 2018
DOI: 10.1186/s12943-018-0878-x
Springer Nature


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.

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