The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance

Abstract

Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell–cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that ‘vesiculome’ data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.

Adenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes

“…The release of EVs from tumor cells supports the ability of GBs to communicate with distant cells. Interestingly, the content of EVs reflects the activation state of the mother cell; hence, tumor cells can proliferate and modulate acceptor cells (Matarredona and Pastor, 2019;Zhang et al, 2019;Schuurmans et al, 2020). Studies of EVs are emerging and have shown promising results regarding their ability to maintain a propitious niche for tumor development, as they can modulate immune, epithelial, and glial cell signaling (Benito-Martin et al, 2015;Whiteside, 2017;Almeida et al, 2019;Boomgarden et al, 2020).…”

Extracellular vesicles: The key for precision medicine in glioblastoma

“… 49 , 52 , 53 Conversely, CSF is a confined compartment that is shielded from the blood by the BBB. It is less in volume and contains fewer EVs from other sources compared to blood 54 ; however, CSF sampling is achievable only through lumbar puncture, which is invasive, painful, distressing, and carries the risk of infection and cerebral herniation, among others. These aspects make it inadvisable to repeat CSF sampling in a close timeframe, while supporting blood as the preferred liquid biopsy sample medium.…”

Liquid Biomarkers for Improved Diagnosis and Classification of CNS Tumors

“…Analyzing the spatial distribution of a target molecule within or around an EV of interest is also currently limited as there are no well-established counterstain equivalents used in the immunofluorescence imaging of adherent cells as EVs generally lack a nucleus or nuclear content and even an actin cytoskeleton. The use of orthogonal techniques such as transmission electron microscopy or mass cytometry may help address or mitigate these limitations [ 146 ].…”