Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective

Abstract

Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.

Keywords: Exosomes; Glioblastoma multiforme; Microvesicles; Perivascular niche; Subventricular zone/neurogenic niche; Tumor microenvironment.

Figure 1.. Extracellular vesicles participation in the communication between glioblastoma cells and non-cancer cells in the neurogenic, immune, and perivascular tumor microenvironment.

Each microenvironment presents niche-specific cell types and pathways that regulate tumor cell behavior. In each tumor microenvironment, there is reciprocal intercellular transport of proteins and microRNAs. Immune cells can release extracellular vesicles with cargo that impacts neural stem cell proliferation, such as cytokines from microglia extracellular vesicles which increase neural stem cell proliferation or EAAT-1 from activated astrocyte extracellular vesicles that decrease neural stem cell proliferation. These astrocytes can also increase tumor cell proliferation and survival with extracellular vesicles containing neuroglobin and alkylguanine DNA alkyltransferase respectively. Neural stem cells of the neurogenic niche can release extracellular that increase activated microglia and their cytokine release. Said neural stem cells also establish a crosstalk between themselves moderating quiescence and adult neurogenesis (miR-9, miRNA-21a, miR-let7b, miR-124, miR-137). Glioblastoma stem cells can manipulate this regulation by releasing extracellular vesicles that transform neural stem cells towards being cancerous. In the perivascular niche, endothelial cells have been seen to release extracellular vesicles containing TGF-β which prompts local glioblastoma stem cells towards differentiating into pericytes. Glioblastoma stem cells are also seen to recruit tumor-associated macrophages to increase tumor growth as well as supporting angiogenesis by increased VEGF.

Figure 2.. Extracellular vesicles biogenesis occurs by invagination or blebbing on the cell membrane originating different vesicle subtypes.

Extracellular vesicle biogenesis differs depending on the sub-population of vesicles in question. Exosomes range from 30–100nm in size, formed by plasma membrane invagination utilizing ESCRT-independent, shown to include ceramides and tetraspanin driven sorting, and ESCRT-dependent pathways, which gathers ubiquitylated cargo using ESCRT protein complexes. The release of exosomes derived from both pathways are influenced by SNARE and Ras-related proteins. Microvesicles are generally larger, ranging from 50–1000nm in size, and form through blebbing and budding on the plasma membrane. Microvesicles share components with exosome formation, including tetraspanins, however cargo in this case is determined by a component’s lipid raft affinity and anchorage to plasma membrane. MVBs fuse with the plasma membrane and release the ILVs into the extracellular space. The budding and consequential release of microvesicles is influenced by Ca2+ levels, ESCRT pathway associated proteins, and ADP-ribosylation factor 6. Exosomes and microvesicles have distinct surface markers to help differentiate the two populations from each other.