Abstract
Diffuse gliomas are lethal tumors of the central nervous system (CNS) characterized by infiltrative growth, aggressive nature, and therapeutic resistance. The recent 2016 WHO classification for CNS tumors categorizes diffuse glioma into two major types that include IDH wild-type glioblastoma, which is the predominant type and IDH-mutant glioblastoma, which is less common and displays better prognosis. Recent studies suggest presence of a distinct cell population with stem cell features termed as glioma stem cells (GSCs) to be causal in driving tumor growth in glioblastoma. The presence of a stem and progenitor population possibly makes glioblastoma highly heterogeneous. Significantly, tumor growth is driven by interaction of cells residing within the tumor with the surrounding milieu termed as the tumor microenvironment. It comprises of various cell types such as endothelial cells, secreted factors, and the surrounding extracellular matrix, which altogether help perpetuate the proliferation of GSCs. One of the important mediators critical to the cross talk is extracellular vesicles (EVs). These nano-sized vesicles play important roles in intercellular communication by transporting bioactive molecules into the surrounding milieu, thereby altering cellular functions and/or reprogramming recipient cells. With the growing information on the contribution of EVs in modulation of the tumor microenvironment, it is important to determine their role in both supporting as well as promoting tumor growth in glioma. In this review, we provide a comprehensive overview of the role of EVs in tumor progression and glioma pathogenesis.
Highlights
Adult diffuse gliomas are histopathologically categorized into grades II–IV as oligodendroglioma, oligo-astrocytoma, astrocytoma, and glioblastoma [1]
Numerous functions are attributed to extracellular vesicles (EVs) in cancer that range from their role in antitumor immunity, drug resistance, metastasis, angiogenesis, and intercellular
EV-mediated transfer and secretion of miRNAs may contribute to glioblastoma heterogeneity [61]
Summary
Adult diffuse gliomas are histopathologically categorized into grades II–IV as oligodendroglioma, oligo-astrocytoma, astrocytoma, and glioblastoma [1]. Tumor propagation is a cumulative effect of the GSC population and their communication with the microenvironment that includes the tumor vasculature, immune cells, and non-stem cells This complex biological network arising from intracellular, intercellular, and distant cell interactions supports growth of aggressive and therapy-resistant glioblastoma tumors. The release of exosomes by tumor suppressor activated pathway 6 (TSAP6) gene occurs in a p53-dependent manner [50] Another posttranslational modification, ISGylation was shown to be important in the control of exosome production ISGylation of MVB proteins such as TSG101 regulated exosome release by triggering MVB colocalization with lysosomes and promoted degradation of MVB proteins [51]. The formation of MVs is controlled by ADP-ribosylation factor 6 and membrane lipid microdomains [52], mechanisms responsible for sorting of cargo into the lumen of MVBs that form exosomes are not fully understood [53]
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