Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation

Choi, Dong-Sic; Lee, Tae Hoon; Spinelli, Cristiana; Chennakrishnaiah, Shilpa; D’Asti, Esterina; Rak, Janusz

doi:10.1016/j.semcdb.2017.01.003

Cited by 106 publications

(133 citation statements)

References 208 publications

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“…Tumor stromal cross-talk could also be explained from potential of TNTs in transferring oncogenic miRNAs via direct connections between cells (Thayanithy et al, 2014b). The similar mode of stromal cross-talk has been shown by EVs (Fatima and Nawaz, 2015; Webber et al, 2015; Choi et al, 2017). Although, EVs are implicated in the transfer of oncogenic miRNAs between cells; however TNT-mediated transfer seems to be distinct form of inter-cellular transfer.…”

Section: Resemblance In Dissemination Of Disease Associated Patternssupporting

confidence: 68%

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

Nawaz

Fatima

2017

Front. Mol. Biosci.

104

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The process of intercellular communication seems to have been a highly conserved evolutionary process. Higher eukaryotes use several means of intercellular communication to address both the changing physiological demands of the body and to fight against diseases. In recent years, there has been an increasing interest in understanding how cell-derived nanovesicles, known as extracellular vesicles (EVs), can function as normal paracrine mediators of intercellular communication, but can also elicit disease progression and may be used for innovative therapies. Over the last decade, a large body of evidence has accumulated to show that cells use cytoplasmic extensions comprising open-ended channels called tunneling nanotubes (TNTs) to connect cells at a long distance and facilitate the exchange of cytoplasmic material. TNTs are a different means of communication to classical gap junctions or cell fusions; since they are characterized by long distance bridging that transfers cytoplasmic organelles and intracellular vesicles between cells and represent the process of heteroplasmy. The role of EVs in cell communication is relatively well-understood, but how TNTs fit into this process is just emerging. The aim of this review is to describe the relationship between TNTs and EVs, and to discuss the synergies between these two crucial processes in the context of normal cellular cross-talk, physiological roles, modulation of immune responses, development of diseases, and their combinatory effects in tissue repair. At the present time this review appears to be the first summary of the implications of the overlapping roles of TNTs and EVs. We believe that a better appreciation of these parallel processes will improve our understanding on how these nanoscale conduits can be utilized as novel tools for targeted therapies.

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Section: Resemblance In Dissemination Of Disease Associated Patternssupporting

confidence: 68%

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

Nawaz

Fatima

2017

Front. Mol. Biosci.

104

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“…We used an isogenic GBM model system where EGFRvIII possesses a strong and well characterized transforming ability and the changes that occur downstream are not obscured by intercellular variability. In this setting, we made several novel observations, which suggest a multifaceted effect of the oncogenic transformation on glioma vesiculation processes, including the molecular regulation of EV biogenesis, as well as their protein composition, molecular heterogeneity, uptake by recipient cells and possible changes in biological activity (17).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic and epigenetic driver events have already been implicated by us and others as regulators of the EV release and intercellular communication in cancer, including intercellular trafficking of transforming mutant macromolecules, such as HRAS, EGFR and EGFRvIII (12,17,18,58,62).…”

Section: Discussionmentioning

confidence: 99%

“…The successive fractions (1 mL each) were collected, starting from the top, to locate the iodixanol density with the highest EV content. This was accomplished through testing fractions for particle counts and sizes by NTA, and by detection of canonical EV marker proteins, such as CD81 (24), using Western blotting ( their regulation may be affected by oncogenic transformation (17). To understand whether such influence is exerted by EGFRvIII, we profiled U373 and U373vIII cells for the expression of 91 vesiculation-related transcripts using a customized RT2 array ( Fig.…”

Section: Changes In Characteristics Of Glioma Cells and Their Evs Folmentioning

confidence: 99%

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The Impact of Oncogenic EGFRvIII on the Proteome of Extracellular Vesicles Released from Glioblastoma Cells

Choi

Montermini

Kim

et al. 2018

Molecular & Cellular Proteomics

Self Cite

128

133

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Epidermal growth factor receptor (EGFR)EGFR SummaryGlioblastoma multiforme (GBM) is a highly aggressive and heterogeneous form of primary brain tumors, driven by a complex repertoire of oncogenic alterations, including the constitutively active epidermal growth factor receptor (EGFRvIII). EGFRvIII impacts both cell-intrinsic and non-cell autonomous aspects of GBM progression, including cell invasion, angiogenesis and modulation of the tumor microenvironment. This is, at least in part, attributable to the release and intercellular trafficking of extracellular vesicles (EVs), heterogeneous membrane structures containing multiple bioactive macromolecules. Here we analyzed the impact of EGFRvIII on the profile of glioma EVs using isogenic tumor cell lines, in which this oncogene exhibits a strong transforming activity. We observed that EGFRvIII expression alters the expression of EV-regulating genes (vesiculome) and EV properties, including their protein composition. Using mass spectrometry, quantitative proteomic analysis and Gene Ontology terms filters, we observed that EVs released by EGFRvIIItransformed cells were enriched for extracellular exosome and focal adhesion related proteins.Among them, we validated the association of pro-invasive proteins (CD44, BSG, CD151) with EVs of EGFRvIII expressing glioma cells, and down-regulation of exosomal markers (CD81 and CD82) relative to EVs of EGFRvIII-negative cells. Nano-flow cytometry revealed that the EV output from individual glioma cell lines was highly heterogeneous, such that only a fraction of vesicles contained specific proteins. Notably, cells expressing EGFRvIII released EVs double positive for CD44/BSG, and these proteins also co-localized in cellular filopodia. We also detected the expression of homophilic adhesion molecules and increased homologous EV uptake by EGFRvIII-positive glioma cells. These results suggest that oncogenic EGFRvIII reprograms the proteome and uptake of GBM-related EVs, a notion with considerable implications for their biological activity and properties relevant for the development of EV-based cancer biomarkers.

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“…Extracellular vesicles (EVs) released from one cell and capable of influencing another (a known method of cell:cell communication) are recognised to be involved in the protein transmission in some of these neuropathies [106,184], and also in tumours [29]. It is clear that the health of CSF and ISF flow and drainage will influence the spread of such aggregated proteins.…”

Section: Cns Pathologies and Disturbances Of Brain Fluidsmentioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation

Cited by 106 publications

References 208 publications

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

The Impact of Oncogenic EGFRvIII on the Proteome of Extracellular Vesicles Released from Glioblastoma Cells

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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