Abstract
Malignant glioma cells invade the surrounding brain parenchyma, by migrating along the blood vessels, thus promoting cancer growth. The biological bases of these activities are grounded in profound alterations of the metabolism and the structural organization of the cells, which consequently acquire the ability to modify the surrounding microenvironment, by altering the extracellular matrix and affecting the properties of the other cells present in the brain, such as normal glial-, endothelial- and immune-cells. Most of the effects on the surrounding environment are probably exerted through the release of a variety of extracellular vesicles (EVs), which contain many different classes of molecules, from genetic material to defined species of lipids and enzymes. EV-associated molecules can be either released into the extracellular matrix (ECM) and/or transferred to neighboring cells: as a consequence, both deep modifications of the recipient cell phenotype and digestion of ECM components are obtained, thus causing cancer propagation, as well as a general brain dysfunction. In this review, we first analyze the main intracellular and extracellular transformations required for glioma cell invasion into the brain parenchyma; then we discuss how these events may be attributed, at least in part, to EVs that, like the pawns of a dramatic chess game with cancer, open the way to the tumor cells themselves.
Highlights
The cancers of the Central Nervous System (CNS) are extremely complex and heterogeneous [1,2,3]
Glioblastomas have been subdivided into: (i) proneural (PN), characterized by mutations in the genes encoding isocitrate dehydrogenase genes 1 and 2 (IDH1/2), platelet derived growth factor receptor α (PDGFRα) and TP53; (ii) neural (N), which express high levels of neuronal markers, such as neurofilament light polypeptide (NEFL) and the synaptic protein synaptotagmin (SYT1); (iii) classical (C), which frequently show amplification of the gene encoding the epidermal growth factor receptor (EGFR) and (iv) mesenchymal (MES), in which mutations in the genes encoding neurofibromin 1 (NF1), a negative regulator of Ras signaling pathway, phosphatase and tensin homolog (PTEN) and TP53 have been reported
For example, which cultured oligodendroglioma cells discard through extracellular vesicles (EVs) the histone variant H1.0, which might otherwise contribute to cell differentiation [298]; on the other hand, the same EVs contain matrix metalloproteases able to digest aggrecan [299]
Summary
The cancers of the Central Nervous System (CNS) are extremely complex and heterogeneous [1,2,3]. A recent classification of gliomas was based on mutations present in specific genes [8,9,10]; in particular, an integrated genomic analysis identified clinically relevant subtypes of glioblastoma, characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1 [11] According to these observations, glioblastomas have been subdivided into: (i) proneural (PN), characterized by mutations in the genes encoding isocitrate dehydrogenase genes 1 and 2 (IDH1/2) (mutations frequently found in secondary glioblastomas), platelet derived growth factor receptor α (PDGFRα) and TP53 (which encodes p53 oncosuppressor protein); (ii) neural (N), which express high levels of neuronal markers, such as neurofilament light polypeptide (NEFL) and the synaptic protein synaptotagmin (SYT1); (iii) classical (C), which frequently show amplification of the gene encoding the epidermal growth factor receptor (EGFR) and (iv) mesenchymal (MES), in which mutations in the genes encoding neurofibromin 1 (NF1), a negative regulator of Ras signaling pathway, phosphatase and tensin homolog (PTEN) and TP53 have been reported. We need a still better knowledge of GBM biological properties and more powerful methods for their as early as possible diagnosis
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