Abstract
Simple SummaryGlioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor. Emerging evidence indicate the multi-faceted role of extracellular vesicles (EVs) in GBM growth and proliferation. In fact, GBM-derived EVs can alter the phenotype of GBM-associated parenchymal cells; thus, promoting tumor growth, angiogenesis, and immune evasion. Remarkably, among several pathways that are frequently deregulated in GBM, mammalian Target of Rapamycin (mTOR) up-regulation, and subsequent autophagy (ATG) depression are considered hallmarks of GBM. In fact, mTOR-dependent ATG inhibition strongly correlates with the presence of EVs, which in turn promotes glioblastoma cancer stem cells (GSCs) self-renewal, proliferation, and infiltration. ATG and exosome release are reciprocally regulated. In detail, a failure in ATG enhances exosomal release. Therefore, strategies aimed at targeting on mTOR-dependent extracellular vesicles could be a promising approach for GBM prevention and treatment.Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.
Highlights
Gliomas are the most frequent intracranial tumors in adults [1]
extracellular vesicles (EVs) released by surrounding stromal cells maintain a supportive niche, which enhances glioblastoma cancer stem cells (GSCs) proliferation and aggressiveness [97]. These cells are not mere bystanders, but they emerge as active players in glioblastoma multiforme (GBM) tumor microenvironment (TME) adaptive remodeling by establishing a dynamic EV-mediated crosstalk with GSCs [123]
This is the case of stromal cells resembling mesenchymal stem cells (MSCs), which recently emerged as a novel stromal component of GBM TME
Summary
Gliomas are the most frequent intracranial tumors in adults [1]. Within this heterogeneous group of neoplasms, glioblastoma multiforme (GBM) represents the highest and most severe prognostic grade, namely “grade IV” glioma, according to the World Health Organization (WHO) classification system [2,3]. Recent findings demonstrate that GBM malignant behavior is associated with the presence of a small subpopulation of cells referred to as glioblastoma cancer stem cells or glioma stem cells (GSCs) [9,10,11] These cells display biological properties of normal neural stem cells, such as increased growth rate, enhanced self-renewal, and pluripotency [12,13]. It has been demonstrated that GBM cells can interact with neighboring or distant cells, either tumorigenic and non-tumorigenic parenchymal ones, such as astrocytes, endothelial cells, pericytes and immune cells [31] (Figure 1) This may occur either through direct cell-to-cell contact (e.g., trogocytosis, tunneling nanotubes, gap junctions) or it may involve the release of extracellular vesicles (EVs), such as microvesicles and endosome-derived exosomes [31].
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