Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes.

Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an important role in cancer. The state of knowledge on biogenesis, molecular content and horizontal communication of diverse types of cancer EVs has expanded considerably in recent years. As a consequence, a plethora of information about EV composition and molecular function has emerged, along with the notion that cancer cells rely on these particles to invade tissues and propagate oncogenic signals at distance. The number of in vivo studies, designed to achieve a deeper understanding of the extent to which EV biology can be applied to clinically relevant settings, is rapidly growing. This review summarizes recent studies on cancer-derived EV functions, with an overview about biogenesis and molecular cargo of exosomes, microvesicles and large oncosomes. We also discuss current challenges and emerging technologies that might improve EV detection in various biological systems. Further studies on the functional role of EVs in specific steps of cancer formation and progression will expand our understanding of the diversity of paracrine signaling mechanisms in malignant growth.

Minciacchi VR ，Freeman MR ，Di Vizio D 《-》

Focus on Extracellular Vesicles: New Frontiers of Cell-to-Cell Communication in Cancer.

Ciardiello C ，Cavallini L ，Spinelli C ，Yang J ，Reis-Sobreiro M ，de Candia P ，Minciacchi VR ，Di Vizio D ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation.

Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker and companion diagnostics. Indeed, studies are underway to further explore the multiple links between molecular causality in cancer and various aspects of cellular vesiculation.

Choi D ，Lee TH ，Spinelli C ，Chennakrishnaiah S ，D'Asti E ，Rak J ... -  《-》

Extracellular Vesicles: Recent Developments in Technology and Perspectives for Cancer Liquid Biopsy.

Nazarenko I 《-》

Extracellular vesicles in the biology of brain tumour stem cells--Implications for inter-cellular communication, therapy and biomarker development.

Extracellular vesicles (EVs) act as carriers of molecular and oncogenic signatures present in subsets of tumour cells and tumour-associated stroma, and as mediators of intercellular communication. These processes likely involve cancer stem cells (CSCs). EVs represent a unique pathway of cellular export and cell-to-cell transfer of insoluble molecular regulators such as membrane receptors, signalling proteins and metabolites, thereby influencing the functional integration of cancer cell populations. While mechanisms that control biogenesis, cargo and uptake of different classes of EVs (exosomes, microvesicles, ectosomes, large oncosomes) are poorly understood, they likely remain under the influence of stress-responses, microenvironment and oncogenic processes that define the biology and heterogeneity of human cancers. In glioblastoma (GBM), recent molecular profiling approaches distinguished several disease subtypes driven by distinct molecular, epigenetic and mutational mechanisms, leading to formation of proneural, neural, classical and mesenchymal tumours. Moreover, molecularly distinct clonal cellular lineages co-exist within individual GBM lesions, where they differentiate according to distinct stem cell hierarchies resulting in several facets of tumour heterogeneity and the related potential for intercellular interactions. Glioma stem cells (GSCs) may carry signatures of either proneural or mesenchymal GBM subtypes and differ in several biological characteristics that are, at least in part, represented by the output and repertoire of EV production (vesiculome). We report that vesiculomes differ between known GBM subtypes. EVs may also reflect and influence the equilibrium of the stem cell hierarchy, contain oncogenic drivers and modulate the microenvironment (vascular niche). The GBM/GSC subtype-specific differentials in EV cargo of proteins, transcripts, microRNA and DNA may enable detection of the dynamics of the stem cell compartment and result in biological effects that remain to be fully characterized.

Nakano I ，Garnier D ，Minata M ，Rak J ... -  《-》