Extracellular Vesicles in Brain Tumor Progression

Abstract

Brain tumors can be viewed as multicellular 'ecosystems' with increasingly recognized cellular complexity and systemic impact. While the emerging diversity of malignant disease entities affecting brain tissues is often described in reference to their signature alterations within the cellular genome and epigenome, arguably these cell-intrinsic changes can be regarded as hardwired adaptations to a variety of cell-extrinsic microenvironmental circumstances. Conversely, oncogenic events influence the microenvironment through their impact on the cellular secretome, including emission of membranous structures known as extracellular vesicles (EVs). EVs serve as unique carriers of bioactive lipids, secretable and non-secretable proteins, mRNA, non-coding RNA, and DNA and constitute pathway(s) of extracellular exit of molecules into the intercellular space, biofluids, and blood. EVs are also highly heterogeneous as reflected in their nomenclature (exosomes, microvesicles, microparticles) attempting to capture their diverse origin, as well as structural, molecular, and functional properties. While EVs may act as a mechanism of molecular expulsion, their non-random uptake by heterologous cellular recipients defines their unique roles in the intercellular communication, horizontal molecular transfer, and biological activity. In the central nervous system, EVs have been implicated as mediators of homeostasis and repair, while in cancer they may act as regulators of cell growth, clonogenicity, angiogenesis, thrombosis, and reciprocal tumor-stromal interactions. EVs produced by specific brain tumor cell types may contain the corresponding oncogenic drivers, such as epidermal growth factor receptor variant III (EGFRvIII) in glioblastoma (and hence are often referred to as 'oncosomes'). Through this mechanism, mutant oncoproteins and nucleic acids may be transferred horizontally between cellular populations altering their individual and collective phenotypes. Oncogenic pathways also impact the emission rates, types, cargo, and biogenesis of EVs, as reflected by preliminary analyses pointing to differences in profiles of EV-regulating genes (vesiculome) between molecular subtypes of glioblastoma, and in other brain tumors. Molecular regulators of vesiculation can also act as oncogenes. These intimate connections suggest the context-specific roles of different EV subsets in the progression of specific brain tumors. Advanced efforts are underway to capture these events through the use of EVs circulating in biofluids as biomarker reservoirs and to guide diagnostic and therapeutic decisions.

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

“…Platelets are known to release microparticles (MP) containing compounds that promote invasiveness of cancer cells and metastatic potential [ 239 ]. It is well recognized that glioblastoma increases risk of thrombotic events that activate platelets and may induce MP-mediated interactions between tumor cells, platelets, and the vasculature.…”

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

“…Their cargo encompasses proteins, RNA, and lipids specific for the cell of origin (3)(4)(5). In the neoplastic setting, they induce tumor progression and infiltration, sustain neoangiogenesis, inhibit immune response, and lead to chemo/radio-resistance (3,(6)(7)(8)(9)(10)(11)(12). Interestingly, extracellular vesicles can be used as circulating biomarkers because they can be easily isolated from bloodstream, urine, cerebrospinal, ascitic, amniotic, and seminal fluid (4).…”

Glioblastoma hijacks microglial gene expression to support tumor growth

“…Tumor cells can alter their milieu in part by releasing extracellular vesicles (EVs), including exosomes and microvesicles [11][12][13]. EVs are a heterogeneous collection of membrane-bound carriers with complex cargoes, including proteins, lipids, and nucleic acids [13][14][15][16].…”