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

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.

Cancer Stem-Like Cells in Glioblastoma

“…The ability of tumor cells to adapt to their environment is of great interest and mechanisms by which tumor cells communicate with their microenvironment are increasingly being investigated. Studies concerning exosomes (vesicles excreted from cells) and their role in cancer progression underline new point of views on tumors including GBM (61,62). Numerous studies are also being performed on the epigenetic profile of tumor cells, which could be involved in cell reprogramming and adaptation to their environment.…”

Exosomes in cancer theranostic: Diamonds in the rough

“…62 Furthermore, TrkB (Tropomyosin receptor kinase B) expression was detected in exosomes isolated from plasma of glioblastoma patients, suggesting that this receptor may be considered also as a new biomarker for glioblastoma diagnosis. 64 It was latter on reported that certain proteins were differentially expressed dependently on the melanoma cells from which the exosomes were analyzed, revealing a specific signature for metastatic cell lines. 65 In this way, in exosomes from patients with metastatic melanoma, MIA (Melanoma Inhibitory Activity) and S100B can be detected, therefore their quantification presents diagnostic and prognostic utility.…”

Spitting out the demons: Extracellular vesicles in glioblastoma

“…46,47,49 Furthermore, a number of recent studies established that, in addition to mRNA and miRNA, proteins can also be examined from plasma-isolated EVs. 21,50 Besides diagnosis purposes, the fact that EVs can somehow mirror tumor progression (please see our previous section) raises the possibility that EVs are suitable for theranostic application, personalized medicine and evaluation of response to treatment. In this regard, the levels of exosomal mRNA collected from plasma correlate with the immunological responses of patients enrolled in a vaccination trial.…”