Extracellular Vesicle-Mediated Communication between the Glioblastoma and Its Microenvironment

Matarredona, Esperanza R.; Pastor, Ángel M.

doi:10.3390/cells9010096

Cited by 66 publications

(71 citation statements)

References 87 publications

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“…In GBM, EV protein-cargo has for example been associated with the phenotypic signature of GBM cells [23], while TMZ treatment has been shown to increase EV release in GBM and to promote more pro-oncogenic EV signatures [24]. Similarly, as in other cancers, GBM cells use EVs for inter-cellular communication in the tumour and to influence the surrounding microenvironment to promote tumour growth, angiogenesis, metabolism and invasion [20,[25][26][27][28][29][30]. The regulation of EV biogenesis has therefore received increasing attention in recent years as an interceptive strategy in cancer, both to sensitize cancer cells to chemotherapy and to limit tumour growth in vivo [8,9,[31][32][33][34][35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

Uysal-Onganer

MacLatchy

Rayan

et al. 2020

IJMS

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Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been highlighted. Here, two GBM cell lines were treated with PAD2, PAD3 and PAD4 isozyme-specific inhibitors. Effects were assessed on extracellular vesicle (EV) signatures, including EV-microRNA cargo (miR21, miR126 and miR210), and on changes in cellular protein expression relevant for mitochondrial housekeeping (prohibitin (PHB)) and cancer progression (stromal interaction molecule 1 (STIM-1) and moesin), as well as assessing cell invasion. Overall, GBM cell-line specific differences for the three PAD isozyme-specific inhibitors were observed on modulation of EV-signatures, PHB, STIM-1 and moesin protein levels, as well as on cell invasion. The PAD3 inhibitor was most effective in modulating EVs to anti-oncogenic signatures (reduced miR21 and miR210, and elevated miR126), to reduce cell invasion and to modulate protein expression of pro-GBM proteins in LN229 cells, while the PAD2 and PAD4 inhibitors were more effective in LN18 cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for deiminated proteins relating to cancer, metabolism and inflammation differed between the two GBM cell lines. Our findings highlight roles for the different PAD isozymes in the heterogeneity of GBM tumours and the potential for tailored PAD-isozyme specific treatment.

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Section: Introductionmentioning

confidence: 99%

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

Uysal-Onganer

MacLatchy

Rayan

et al. 2020

IJMS

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“…Supporting the importance of cell–cell interactions in glioma, the requirement for two oncogenes to drive tumor formation (i.e., RasV12, scribbled ) can be achieved even when these genes are not expressed in the same cells, but rather in neighboring clones [ 144 ]. Since then, several studies have revealed the role that EVs play in mediating cell–cell interactions in glioma, as elegantly reviewed [ 145 , 146 ].…”

Section: Role Of Tumor-derived Evs In Gliomamentioning

confidence: 99%

“…Numerous studies have reported the non-cell autonomous effects of GBM tumor-derived EVs on neural cells present in the tumor microenvironment, including astrocytes, endothelial cells and pericytes ( Figure 2 ) [ 145 , 146 ]. Some key studies are worth mentioning due to their emerging role as biomarkers for clinical staging and treatment response.…”

Section: Role Of Tumor-derived Evs In Gliomamentioning

confidence: 99%

“…Patient-derived ODG cell lines secrete EVs [ 175 ], but only a handful of studies have examined their roles in ODG tumorigenicity [ 176 , 177 ]. Strikingly, instead of the growth-promoting effects largely attributed to GBM EVs [ 145 , 146 ], EVs derived from a mouse G26/24 ODG cell line have cytotoxic effects on neurons and to a lesser extent, astrocytes in vitro [ 176 , 177 ]. Two pro-apoptotic proteins were identified in G26/24 ODG-EVs that contribute to their cytotoxic effects—Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [ 176 , 177 ].…”

Section: Role Of Tumor-derived Evs In Gliomamentioning

confidence: 99%

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The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance

Balakrishnan

Roy²,

Fleming

et al. 2020

Cancers

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Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell–cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that ‘vesiculome’ data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.

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“…EVs are secreted by most if not all cells in the brain, including oligodendrocytes 14 , astrocytes 15 , neurons 16 , as well as cancerous cells 17 . There are now several examples of glioma cells interacting with cells in the tumor niche via EVs 18,19 . Strikingly, while EVs from higher-grade gliomas are generally growth promoting, the few studies conducted with ODG suggest that ODG-derived EVs may be cytotoxic 20,21 .…”

Section: Introductionmentioning

confidence: 99%

SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

Balakrishnan

Adnani

Chinchalongporn

et al. 2020

Preprint

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Oligodendrogliomas are lower-grade, slow-growing gliomas that are ultimately fatal. Although driver mutations are known, the mechanisms underlying their signature slow growth rates are poorly understood. We found evidence for intra-tumoral interactions between neoplastic and non-neoplastic cells in oligodendroglioma tissues. To further study these cell interactions, we used two patient-derived oligodendroglioma cell lines of lower and higher aggressivity. Both oligodendroglioma cell lines released extracellular vesicles that had cytotoxic effects on non-neoplastic and neoplastic cells, but each had distinct vesicular proteomes. Consistent with extracellular vesicles mediating growth inhibitory effects in oligodendrogliomas, higher expression levels of several extracellular vesicle biogenesis genes (SMPD3, TSG101, STAM1) correlates with longer survival in oligodendroglioma patients. Furthermore, SMPD3 overexpression slows oligodendroglioma cell growth in culture. Conversely, SMPD3 knockdown enhances oligodendroglioma proliferation in vitro, in murine xenografts, and in human cerebral organoid co-cultures. Oligodendroglioma-derived extracellular vesicles thus mediate tumor cell microenvironmental interactions that contribute to low aggressivity.

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Extracellular Vesicle-Mediated Communication between the Glioblastoma and Its Microenvironment

Cited by 66 publications

References 87 publications

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance

SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

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