Extracellular Vesicles in Brain Tumor Progression

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.

exosomes

Heterogeneity of extracellular vesicle profiles in brain tumors. Several processes may influence the heterogeneity of extracellular vesicles (EVs) produced by brain tumors. This includes heterogeneity of disease entities and of cancer cells, diversity of vesiculation processes driven by intrinsic cellular networks, including oncogenic pathways, and their modulation by the microenvironment and therapeutic interventions. As detailed in the text, EV heterogeneity encompasses emission rates, types of EVs released (exosomes, ectosomes, other vesicles), their molecular cargo (oncogenic proteins and nucleic acids, effector molecules), and biological activities. Tumor stoma may also contribute to the unique signature and function of EVs in brain tumors. For example glioblastoma (GBM) exists in four molecular subtypes (PN, NEU, MES, CL) driven by different oncogenic pathways, which includes different expression profiles of vesiculation-regulating genes (vesiculomes)

D’Asti E, Chennakrishnaiah S, Lee TH, Rak J. (2016) Extracellular Vesicles in Brain Tumor Progression. Cell Mol Neurobiol [Epub ahead of print]. [abstract]

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