TrkB-containing exosomes promote the transfer of glioblastoma aggressiveness to YKL-40-inactivated glioblastoma cells.

Sandra Pinet,Nicolas Vedrenne,Marie-Odile Jauberteau,Serge Battu,Laurence Richard,Barbara Bessette,Fabrice Lalloué,Aurélie Lacroix

doi:10.18632/oncotarget.10387

Abstract

The neurotrophin receptors are known to promote growth and proliferation of glioblastoma cells. Their functions in spreading glioblastoma cell aggressiveness to the microenvironment through exosome release from glioblastoma cells are unknown.Considering previous reports demonstrating that YKL-40 expression is associated with undifferentiated glioblastoma cancer stem cells, we used YKL-40-silenced cells to modulate the U87-MG differentiated state and their biological aggressiveness. Herein, we demonstrated a relationship between neurotrophin-receptors and YKL-40 expression in undifferentiated cells. Differential functions of cells and derived-exosomes were evidenced according to neurotrophin receptor content and differentiated cell state by comparison with control pLKO cells.YKL-40 silencing of glioblastoma cells impairs proliferation, neurosphere formation, and their ability to induce endothelial cell (HBMEC) migration. The modulation of differentiated cell state in YKL-40-silenced cells induces a decrease of TrkB, sortilin and p75NTR cellular expressions, associated with a low-aggressiveness phenotype. Interestingly, TrkB expressed in exosomes derived from control cells was undetectable in exosomes from YKL-40 -silenced cells. The transfer of TrkB-containing exosomes in YKL-40-silenced cells contributed to restore cell proliferation and promote endothelial cell activation. Interestingly, in U87 MG xenografted mice, TrkB-depleted exosomes from YKL-40-silenced cells inhibited tumor growth in vivo.These data highlight that TrkB-containing exosomes play a key role in the control of glioblastoma progression and aggressiveness. Furthermore, TrkB expression was detected in exosomes isolated from plasma of glioblastoma patients, suggesting that this receptor may be considered as a new biomarker for glioblastoma diagnosis.

Highlights

Glioblastoma (GBM), the most frequent type of malignant tumor in the adult central nervous system, is associated with poor prognosis with a mean survival of 12 months despite advances in surgery, radiotherapy and chemotherapy [1, 2]
We have previously shown that CHI3L1 is overexpressed in undifferentiated U87-MG cells and in neurosphere-forming glioblastoma stem cells, isolated from GBM patients [30]
According that TrkB expression was detected in exosomes from glioblastoma cells in cultures; we have extended this study to exosomes from glioblastoma patients

Summary

Introduction

Glioblastoma (GBM), the most frequent type of malignant tumor in the adult central nervous system, is associated with poor prognosis with a mean survival of 12 months despite advances in surgery, radiotherapy and chemotherapy [1, 2]. The cellular heterogeneity of tumors containing glioblastoma stem cells (GSC) ( named brain tumor initiating cells) have been reported in GBM [5, 6]. Their ability to remodel actively their microenvironment, contributes to promote tumorigenesis [7]. The exosomes released from tumor cells are described to control the microenvironment. These small bilayer microvesicles (50–150 nm in size) have been extensively studied for their ability to transfer www.impactjournals.com/oncotarget molecular cargo to surrounding cells, influencing the tumor phenotype [8, 9]. The transfer of oncogenic receptors such as EGFRvIII in GBM contributes to spread aggressiveness to microenvironment via exosomes [8]

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Results

Conclusion