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.
Highlights
Glioblastoma (GBM) is the most aggressive type of primary brain tumours
The mean ± SEM of 3 independent experiments is shown. c Western blotting validation of the human IgG, Annexin A2 and CD44 in Extracellular vesicles (EVs) derived from LN18 and U87 GBM cells. d Gene expression distribution of Annexin A2 and CD44 among the different GBM subtypes has been obtained from The Cancer Genome Atlas (TCGA)
Bevacizumab affects the EVs proteomic content derived from GBM cells Since Vascular Endothelial Growth Factor-A (VEGF-A) represents the main target of bevacizumab and in order to determine the best model for our study, we examined the expression of different components of the VEGF-A signalling in three different GBM cell lines
Summary
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. It has been observed that cetuximab, an EGF-R monoclonal IgG1 antibody, is associated with extracellular vesicles (EVs) derived from treated cancer cells suggesting that such processes could be implicated in tumour limited response to therapy [4]. (See figure on previous page.) Fig. 1 IgG1/Bevacizumab antibody can affect LN18 and U87 GBM cells-derived EVs concentration and their proteomic content.
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