Rôle du transfert des récepteurs des neurotrophines via les exosomes dans l'agressivité du glioblastome et le contrôle du microenvironnement

Abstract : Glioblastoma are tumors derived from astrocytes with a dark prognosis. Current therapies fail to inhibit relapses due to radioresistant properties of cancer stem cells (CSC). Communication between CSC and their microenvironment is required for maintain “stem cells niche” and cell survival . The transfer of materials between CSC, tumor cells and microenvironment contributes to therapeutic resistance. In glioma, recent studies reveal the major role of TrkB and TrkC in survival of CSC. Our previous work, in lung cancer, have shown that neurotrophin receptors exhibits a control on microenvironment cells and angiogenesis through exosome transfer. However, similar mechanism of oncogenic receptor transfer from CSC has never been studied. Our main goal was to determine the involvement of neurotrophin receptors in the transfer of biological aggressiveness to microenvironment cells in order to promote therapeutic resistance in glioblastoma. Our findings suggest a relationship between cell differentiation status, expression of neurotrophin receptors and their interaction with the microenvironment through exosomes. TrkB-containing exosomes play a key role in the control of glioblastoma progression and cell aggressiveness. Mechanisms of radioresistance might also be dependent of the transfer of neurotrophin receptors through exosomes. Indeed, our results on irradiated human GBM cells and treated by exosomes demonstrate the involvement of exosome in radioresistance mechanisms. Although mesenchymal stem cells (MSCs) are considered as stromal components of glioblastoma, their communication with CSC, particularly through exosomes, remain largely undefined. Our results show that GBM-derived exosomes modify the phenotype of MSCs and increase their proliferative and migratory abilities. The putative function of neurotrophin receptors transfer should be analyzed in these models to determine their prime role in glioblastoma pathogenesis and progression. This finding suggest that the neurotrophin receptor expression in exosomes could be used as diagnostis and prognosis biomarkers of GBM.
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Sandra Pinet. Rôle du transfert des récepteurs des neurotrophines via les exosomes dans l'agressivité du glioblastome et le contrôle du microenvironnement. Médecine humaine et pathologie. Université de Limoges, 2016. Français. ⟨NNT : 2016LIMO0039⟩. ⟨tel-01588778⟩

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