Abstract
The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.
Highlights
In this regard, the International Society for Extracellular Vesicles (ISEV) updated its Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines for the field in 2018, based on the evolution of the collective knowledge
In 2019, for example, Jeppesen D.K. et al [10] wrote a “reassessment of exosome composition” in which they described exosomes as endosome-derived small extracellular vesicles” (EV) (40–150 nm). They specified that several molecules are actively and selectively incorporated into intraluminal vesicles (ILV), which reside within multivesicular bodies (MVB), and are released into the extracellular space as exosomes, after fusion with plasma membrane
The authors demonstrated that mesenchymal stem cell (MSC) cultured with EV derived from metastatic NB cell lines showed an up-regulation of miR-375, confirming the role of NB-derived EV in the increase of the osteogenic potential of MSC, which is related to the metastatic spread of NB in the bone marrow (BM) [51]
Summary
An Overview The extracellular space of multi-cellular organisms contains solutions composed of metabolites, ions, proteins and polysaccharides, and of a wide range of membraneenclosed vesicles, henceforward referred as to “extracellular vesicles” (EV). The society specified that, in the absence of specific markers of reliable sub-cellular origin within the experimental systems, it was necessary to use operative terms for the subtypes of EV These terms referred to the physical characteristics of the vesicles such as size (small EV and medium/large EV) or density (low, middle, high), in association with biochemical composition (CD9, CD63, CD81, ALIX, TSG101, HSPs, phosphatidylserine, Annexins) and/or description of conditions/cell origin “in the place of terms such as exosome and microvesicle that are historically burdened by both manifold, contradictory definitions and inaccurate expectations of unique biogenesis” [9]. O’Brien et al [12] distinguished between four major subclasses of EV according to their different biogenesis pathways and size They referred to (i) exosomes (50–150 nm), (ii) MV (100–1000 nm), (iii) apoptotic bodies (100–5000 nm) and (iv) large oncosomes (1000–10,000 nm) containing abnormal and transforming macromolecules as well as other cargo [12]. Several genes implicated in neuronal differentiation were found to be over-expressed in low-risk tumors, whereas identification of novel prognostic markers for high-risk tumors or novel therapeutic targets is still a work in progress [32,33]
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