Special Issue "Extracellular Vesicles: Biogenesis, Cargo and Disease"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: closed (31 August 2021).

Special Issue Editors

Prof. Dr. Suresh Mathivanan
E-Mail Website
Guest Editor
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia
Interests: extracellular vesicles; exosomes; cancer biology; cancer cell proteomics; metastasis; bioinformatics
Special Issues, Collections and Topics in MDPI journals
Dr. Pamali Fonseka
E-Mail Website
Assistant Guest Editor
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
Interests: extracellular vesicles; exosomes; ectosomes; cancer signaling; cancer; intercellular communication; cell migration; EMT; wnt; metastasis

Special Issue Information

Dear Colleagues, 

Extracellular vesicles (EVs) are membranous vesicles of 30–5000 nm in size. EVs are heterogeneous and are secreted into the extracellular matrix by the cells under both physiological and pathological conditions. These EVs can be divided into three categories based on their biogenesis; exosomes, ectosomes, or shedding microvesicles and apoptotic bodies. Recent studies have identified EVs as critical players in intercellular communication. EVs carry a rich cargo of proteins, nucleic acids, lipids, and metabolites constantly mirroring the cell of origin and can potentially moderate various signaling pathways in the recipient cells. EVs have been isolated from a variety of biological fluids including saliva, blood, urine, bile, and milk. The occurrence of enriched proteins and RNA in EVs highlights the existence of specific sorting mechanisms that contribute to the selective packaging of various cargo. However, due to the lack of comprehensive functional studies regarding the molecular machinery of cargo sorting, these complex mechanisms remain poorly understood. Due to the emerging role of EVs in diseases, it is vital to understand the sorting of EV cargo to exploit EVs for drug delivery and inhibit/decrease disease progression.

This Special Issue focusses on recent findings pertaining to EV biogenesis, characterization of EV cargo, and the role of EVs in disease progression. We warmly welcome experts to submit previously unpublished original scientific research with novel findings and reviews with a comprehensive overview of EVs.

Prof. Suresh Mathivanan
Dr. Pamali Fonseka
Guest Editors

Manuscript Submission Information

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Keywords

  • exosomes
  • ectosomes
  • apoptotic bodies
  • extracellular vesicles
  • intercellular communication
  • EV biogenesis
  • EV cargo
  • drug delivery
  • EMT
  • metastasis
  • cell–cell signaling
  • biomarkers
  • proteomics
  • transcriptomics
  • EV cargo sorting
  • disease
  • neurodegenerative diseases
  • cancer
  • immunology

Published Papers (16 papers)

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Research

Jump to: Review

Article
Temporal Quantitative Proteomics Analysis of Neuroblastoma Cells Treated with Bovine Milk-Derived Extracellular Vesicles Highlights the Anti-Proliferative Properties of Milk-Derived Extracellular Vesicles
Cells 2021, 10(4), 750; https://doi.org/10.3390/cells10040750 - 29 Mar 2021
Cited by 1 | Viewed by 1156
Abstract
Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the [...] Read more.
Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Panax ginseng-Derived Extracellular Vesicles Facilitate Anti-Senescence Effects in Human Skin Cells: An Eco-Friendly and Sustainable Way to Use Ginseng Substances
Cells 2021, 10(3), 486; https://doi.org/10.3390/cells10030486 - 24 Feb 2021
Cited by 5 | Viewed by 1310
Abstract
Ginseng is a traditional herbal medicine in eastern Asian countries. Most active constituents in ginseng are prepared via fermentation or organic acid pretreatment. Extracellular vesicles (EVs) are released by most organisms from prokaryotes to eukaryotes and play central roles in intra- and inter-species [...] Read more.
Ginseng is a traditional herbal medicine in eastern Asian countries. Most active constituents in ginseng are prepared via fermentation or organic acid pretreatment. Extracellular vesicles (EVs) are released by most organisms from prokaryotes to eukaryotes and play central roles in intra- and inter-species communications. Plants produce EVs upon exposure to microbes; however, their direct functions and utility for human health are barely known, except for being proposed as delivery vehicles. In this study, we isolated EVs from ginseng roots (GrEVs) or the culture supernatants of ginseng cells (GcEVs) derived from Panax ginseng C.A. Meyer and investigated their biological effects on human skin cells. GrEV or GcEV treatments improved the replicative senescent or senescence-associated pigmented phenotypes of human dermal fibroblasts or ultraviolet B radiation-treated human melanocytes, respectively, by downregulating senescence-associated molecules and/or melanogenesis-related proteins. Based on comprehensive lipidomic analysis using liquid chromatography mass spectrometry, the lipidomic profile of GrEVs differed from that of the parental root extracts, showing significant increases in 70 of 188 identified lipid species and prominent increases in diacylglycerols, some phospholipids (phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine), and sphingomyelin, revealing their unique vesicular properties. Therefore, our results imply that GEVs represent a novel type of bioactive and sustainable nanomaterials that can be applied to human tissues for improving tissue conditions and targeted delivery of active constituents. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Importance of between and within Subject Variability in Extracellular Vesicle Abundance and Cargo when Performing Biomarker Analyses
Cells 2021, 10(3), 485; https://doi.org/10.3390/cells10030485 - 24 Feb 2021
Cited by 3 | Viewed by 935
Abstract
Small extracellular vesicles (sEV) have emerged as a potential rich source of biomarkers in human blood and present the intriguing potential for a ‘liquid biopsy’ to track disease and the effectiveness of interventions. Recently, we have further demonstrated the potential for EV derived [...] Read more.
Small extracellular vesicles (sEV) have emerged as a potential rich source of biomarkers in human blood and present the intriguing potential for a ‘liquid biopsy’ to track disease and the effectiveness of interventions. Recently, we have further demonstrated the potential for EV derived biomarkers to account for variability in drug exposure. This study sought to evaluate the variability in abundance and cargo of global and liver-specific circulating sEV, within (diurnal) and between individuals in a cohort of healthy subjects (n = 10). We present normal ranges for EV concentration and size and expression of generic EV protein markers and the liver-specific asialoglycoprotein receptor 1 (ASGR1) in samples collected in the morning and afternoon. EV abundance and cargo was generally not affected by fasting, except CD9 which exhibited a statistically significant increase (p = 0.018). Diurnal variability was observed in the expression of CD81 and ASGR1, which significantly decreased (p = 0.011) and increased (p = 0.009), respectively. These results have potential implications for study sampling protocols and normalisation of biomarker data when considering the expression of sEV derived cargo as a biomarker strategy. Specifically, the novel finding that liver-specific EVs exhibit diurnal variability in healthy subjects should have broad implications in the study of drug metabolism and development of minimally invasive biomarkers for liver disease. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Feasibility of Mechanical Extrusion to Coat Nanoparticles with Extracellular Vesicle Membranes
Cells 2020, 9(8), 1797; https://doi.org/10.3390/cells9081797 - 29 Jul 2020
Cited by 10 | Viewed by 1583
Abstract
Biomimetic functionalization to confer stealth and targeting properties to nanoparticles is a field of intense study. Extracellular vesicles (EV), sub-micron delivery vehicles for intercellular communication, have unique characteristics for drug delivery. We investigated the top-down functionalization of gold nanoparticles with extracellular vesicle membranes, [...] Read more.
Biomimetic functionalization to confer stealth and targeting properties to nanoparticles is a field of intense study. Extracellular vesicles (EV), sub-micron delivery vehicles for intercellular communication, have unique characteristics for drug delivery. We investigated the top-down functionalization of gold nanoparticles with extracellular vesicle membranes, including both lipids and associated membrane proteins, through mechanical extrusion. EV surface-exposed membrane proteins were confirmed to help avoid unwanted elimination by macrophages, while improving autologous uptake. EV membrane morphology, protein composition and orientation were found to be unaffected by mechanical extrusion. We implemented complementary EV characterization methods, including transmission- and immune-electron microscopy, and nanoparticle tracking analysis, to verify membrane coating, size and zeta potential of the EV membrane-cloaked nanoparticles. While successful EV membrane coating of the gold nanoparticles resulted in lower macrophage uptake, low yield was found to be a significant downside of the extrusion approach. Our data incentivize more research to leverage EV membrane biomimicking as a unique drug delivery approach in the near future. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Characteristics of Extracellular Vesicles Released by the Pathogenic Yeast-Like Fungi Candida glabrata, Candida parapsilosis and Candida tropicalis
Cells 2020, 9(7), 1722; https://doi.org/10.3390/cells9071722 - 18 Jul 2020
Cited by 12 | Viewed by 1868
Abstract
Candida spp. yeast-like fungi are opportunistic pathogens in humans and have been recently found to release extracellular vesicles (EVs) that are involved in many vital biological processes in fungal cells. These include communication between microorganisms and host–pathogen interactions during infection. The production of [...] Read more.
Candida spp. yeast-like fungi are opportunistic pathogens in humans and have been recently found to release extracellular vesicles (EVs) that are involved in many vital biological processes in fungal cells. These include communication between microorganisms and host–pathogen interactions during infection. The production of EVs and their content have been significantly characterized in the most common candidal species Candida albicans, including the identification of numerous virulence factors and cytoplasmic proteins in the EV cargo. We have here conducted the isolation and proteomic characterization of EVs produced by the clinically important non-albicans Candida species C. glabrata, C. tropicalis and C. parapsilosis. With the use of ultracentrifugation of the cell-free culture supernatant, the candidal EVs were collected and found to be a heterogeneous population of particles for each species with sizes ranging from 60–280 nm. The proteinaceous contents of these vesicles were analyzed using LC-MS/MS, with particular attention paid to surface-expressed proteins that would come into immediate and direct contact with host cells. We thereby identified 42 extracellular and surface-connected proteins from C. glabrata, 33 from C. parapsilosis, and 34 from C. tropicalis, including membrane-associated transporters, glycoproteins and enzymes involved in the organization of the fungal cell wall, as well as several cytoplasmic proteins, including alcohol dehydrogenase, enolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase and pyruvate kinase, for which the vesicular transport is a possible mechanism underlying their non-classical secretion. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Exosome-Derived LINC00960 and LINC02470 Promote the Epithelial-Mesenchymal Transition and Aggressiveness of Bladder Cancer Cells
Cells 2020, 9(6), 1419; https://doi.org/10.3390/cells9061419 - 07 Jun 2020
Cited by 11 | Viewed by 1410
Abstract
Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer [...] Read more.
Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Exploring Extracellular Vesicles Biogenesis in Hypothalamic Cells through a Heavy Isotope Pulse/Trace Proteomic Approach
Cells 2020, 9(5), 1320; https://doi.org/10.3390/cells9051320 - 25 May 2020
Cited by 4 | Viewed by 1404
Abstract
Studies have shown that the process of extracellular vesicles (EVs) secretion and lysosome status are linked. When the lysosome is under stress, the cells would secrete more EVs to maintain cellular homeostasis. However, the process that governs lysosomal activity and EVs secretion remains [...] Read more.
Studies have shown that the process of extracellular vesicles (EVs) secretion and lysosome status are linked. When the lysosome is under stress, the cells would secrete more EVs to maintain cellular homeostasis. However, the process that governs lysosomal activity and EVs secretion remains poorly defined and we postulated that certain proteins essential for EVs biogenesis are constantly synthesized and preferentially sorted to the EVs rather than the lysosome. A pulsed stable isotope labelling of amino acids in cell culture (pSILAC) based quantitative proteomics methodology was employed to study the preferential localization of the newly synthesized proteins into the EVs over lysosome in mHypoA 2/28 hypothalamic cell line. Through proteomic analysis, we found numerous newly synthesized lysosomal enzymes—such as the cathepsin proteins—that preferentially localize into the EVs over the lysosome. Chemical inhibition against cathepsin D promoted EVs secretion and a change in the EVs protein composition and therefore indicates its involvement in EVs biogenesis. In conclusion, we applied a heavy isotope pulse/trace proteomic approach to study EVs biogenesis in hypothalamic cells. The results demonstrated the regulation of EVs secretion by the cathepsin proteins that may serve as a potential therapeutic target for a range of neurological disorder associated with energy homeostasis. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Angiogenic Activity of Cytochalasin B-Induced Membrane Vesicles of Human Mesenchymal Stem Cells
Cells 2020, 9(1), 95; https://doi.org/10.3390/cells9010095 - 30 Dec 2019
Cited by 11 | Viewed by 2125
Abstract
The cytochalasin B-induced membrane vesicles (CIMVs) are suggested to be used as a vehicle for the delivery of therapeutics. However, the angiogenic activity and therapeutic potential of human mesenchymal stem/stromal cells (MSCs) derived CIMVs (CIMVs-MSCs) remains unknown. Objectives: The objectives of this study [...] Read more.
The cytochalasin B-induced membrane vesicles (CIMVs) are suggested to be used as a vehicle for the delivery of therapeutics. However, the angiogenic activity and therapeutic potential of human mesenchymal stem/stromal cells (MSCs) derived CIMVs (CIMVs-MSCs) remains unknown. Objectives: The objectives of this study were to analyze the morphology, size distribution, molecular composition, and angiogenic properties of CIMVs-MSCs. Methods: The morphology of CIMVs-MSC was analyzed by scanning electron microscopy. The proteomic analysis, multiplex analysis, and immunostaining were used to characterize the molecular composition of the CIMVs-MSCs. The transfer of surface proteins from a donor to a recipient cell mediated by CIMVs-MSCs was demonstrated using immunostaining and confocal microscopy. The angiogenic potential of CIMVs-MSCs was evaluated using an in vivo approach of subcutaneous implantation of CIMVs-MSCs in mixture with Matrigel matrix. Results: Human CIMVs-MSCs retain parental MSCs content, such as growth factors, cytokines, and chemokines: EGF, FGF-2, Eotaxin, TGF-α, G-CSF, Flt-3L, GM-CSF, Fractalkine, IFNα2, IFN-γ, GRO, IL-10, MCP-3, IL-12p40, MDC, IL-12p70, IL-15, sCD40L, IL-17A, IL-1RA, IL-1a, IL-9, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP_1a, MIP-1b, TNF-α, TNF-β, VEGF. CIMVs-MSCs also have the expression of surface receptors similar to those in parental human MSCs (CD90+, CD29+, CD44+, CD73+). Additionally, CIMVs-MSCs could transfer membrane receptors to the surfaces of target cells in vitro. Finally, CIMVs-MSCs can induce angiogenesis in vivo after subcutaneous injection into adult rats. Conclusions: Human CIMVs-MSCs have similar content, immunophenotype, and angiogenic activity to those of the parental MSCs. Therefore, we believe that human CIMVs-MSCs could be used for cell free therapy of degenerative diseases. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Article
Cigarette Smoke Condensate Exposure Changes RNA Content of Extracellular Vesicles Released from Small Airway Epithelial Cells
Cells 2019, 8(12), 1652; https://doi.org/10.3390/cells8121652 - 17 Dec 2019
Cited by 6 | Viewed by 1598
Abstract
Exposure to environmental tobacco smoke (ETS) is a known risk factor for the development of chronic lung diseases, cancer, and the exacerbation of viral infections. Extracellular vesicles (EVs) have been identified as novel mediators of cell–cell communication through the release of biological content. [...] Read more.
Exposure to environmental tobacco smoke (ETS) is a known risk factor for the development of chronic lung diseases, cancer, and the exacerbation of viral infections. Extracellular vesicles (EVs) have been identified as novel mediators of cell–cell communication through the release of biological content. Few studies have investigated the composition/function of EVs derived from human airway epithelial cells (AECs) exposed to cigarette smoke condensate (CSC), as surrogates for ETS. Using novel high-throughput technologies, we identified a diverse range of small noncoding RNAs (sncRNAs), including microRNA (miRNAs), Piwi-interacting RNA (piRNAs), and transfer RNA (tRNAs) in EVs from control and CSC-treated SAE cells. CSC treatment resulted in significant changes in the EV content of miRNAs. A total of 289 miRNAs were identified, with five being significantly upregulated and three downregulated in CSC EVs. A total of 62 piRNAs were also detected in our EV preparations, with five significantly downregulated and two upregulated in CSC EVs. We used TargetScan and Gene Ontology (GO) analysis to predict the biological targets of hsa-miR-3913-5p, the most represented miRNA in CSC EVs. Understanding fingerprint molecules in EVs will increase our knowledge of the relationship between ETS exposure and lung disease, and might identify potential molecular targets for future treatments. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review

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Review
Role of Extracellular Vesicles in Cell Death and Inflammation
Cells 2021, 10(10), 2663; https://doi.org/10.3390/cells10102663 - 05 Oct 2021
Viewed by 812
Abstract
Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial [...] Read more.
Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
EV Cargo Sorting in Therapeutic Development for Cardiovascular Disease
Cells 2021, 10(6), 1500; https://doi.org/10.3390/cells10061500 - 15 Jun 2021
Cited by 2 | Viewed by 948
Abstract
Cardiovascular disease remains the leading cause of morbidity and mortality in the world. Thus, therapeutic interventions to circumvent this growing burden are of utmost importance. Extracellular vesicles (EVs) actively secreted by most living cells, play a key role in paracrine and endocrine intercellular [...] Read more.
Cardiovascular disease remains the leading cause of morbidity and mortality in the world. Thus, therapeutic interventions to circumvent this growing burden are of utmost importance. Extracellular vesicles (EVs) actively secreted by most living cells, play a key role in paracrine and endocrine intercellular communication via exchange of biological molecules. As the content of secreted EVs reflect the physiology and pathology of the cell of their origin, EVs play a significant role in cellular homeostasis, disease pathogenesis and diagnostics. Moreover, EVs are gaining popularity in clinics as therapeutic and drug delivery vehicles, transferring bioactive molecules such as proteins, genes, miRNAs and other therapeutic agents to target cells to treat diseases and deter disease progression. Despite our limited but growing knowledge of EV biology, it is imperative to understand the complex mechanisms of EV cargo sorting in pursuit of designing next generation EV-based therapeutic delivery systems. In this review, we highlight the mechanisms of EV cargo sorting and methods of EV bioengineering and discuss engineered EVs as a potential therapeutic delivery system to treat cardiovascular disease. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer
Cells 2020, 9(12), 2639; https://doi.org/10.3390/cells9122639 - 08 Dec 2020
Cited by 5 | Viewed by 1220
Abstract
Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the [...] Read more.
Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
Mechanisms of Action of EGFR Tyrosine Kinase Receptor Incorporated in Extracellular Vesicles
Cells 2020, 9(11), 2505; https://doi.org/10.3390/cells9112505 - 19 Nov 2020
Cited by 4 | Viewed by 1562
Abstract
EGFR and some of the cognate ligands extensively traffic in extracellular vesicles (EVs) from different biogenesis pathways. EGFR belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in [...] Read more.
EGFR and some of the cognate ligands extensively traffic in extracellular vesicles (EVs) from different biogenesis pathways. EGFR belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in several of the most frequent malignancies such as non-small cell lung cancer, breast cancer, colorectal cancer and ovarian cancer. The carrier EVs exert crucial biological effects on recipient cells, impacting immunity, pre-metastatic niche preparation, angiogenesis, cancer cell stemness and horizontal oncogene transfer. While EV-mediated EGFR signalling is important to EGFR-driven cancers, little is known about the precise mechanisms by which TKRs incorporated in EVs play their biological role, their stoichiometry and associations to other proteins relevant to cancer pathology and EV biogenesis, and their means of incorporation in the target cell. In addition, it remains unclear whether different subtypes of EVs incorporate different complexes of TKRs with specific functions. A raft of high spatial and temporal resolution methods is emerging that could solve these and other questions regarding the activity of EGFR and its ligands in EVs. More importantly, methods are emerging to block or mitigate EV activity to suppress cancer progression and drug resistance. By highlighting key findings and areas that remain obscure at the intersection of EGFR signalling and EV action, we hope to cross-fertilise the two fields and speed up the application of novel techniques and paradigms to both. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
The Role of Exosomes in the Crosstalk between Adipocytes and Liver Cancer Cells
Cells 2020, 9(9), 1988; https://doi.org/10.3390/cells9091988 - 29 Aug 2020
Cited by 7 | Viewed by 1601
Abstract
Exosomes are membrane-bound extracellular vesicles (EVs) that transport bioactive materials between cells and organs. The cargo delivered by exosomes can alter a wide range of cellular responses in recipient cells and play an important pathophysiological role in human cancers. In hepatocellular carcinoma (HCC), [...] Read more.
Exosomes are membrane-bound extracellular vesicles (EVs) that transport bioactive materials between cells and organs. The cargo delivered by exosomes can alter a wide range of cellular responses in recipient cells and play an important pathophysiological role in human cancers. In hepatocellular carcinoma (HCC), for example, adipocyte- and tumor-secreted factors contained in exosomes contribute to the creation of a chronic inflammatory state, which contributes to disease progression. The exosome-mediated crosstalk between adipocytes and liver cancer cells is a key aspect of a dynamic tumor microenvironment. In this review, we summarize the role of increased adiposity and the role of adipocyte-derived exosomes (AdExos) and HCC-derived exosomes (HCCExos) in the modulation of HCC progression. We also discuss recent advances regarding how malignant cells interact with the surrounding adipose tissue and employ exosomes to promote a more aggressive phenotype. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo
Cells 2020, 9(7), 1601; https://doi.org/10.3390/cells9071601 - 02 Jul 2020
Cited by 19 | Viewed by 1628
Abstract
Extracellular vesicles (EVs) mediate cell-to-cell communication via the transfer of biomolecules locally and systemically between organs. It has been elucidated that the specific EV cargo load is fundamental for cellular response upon EV delivery. Therefore, revealing the specific molecular machinery that functionally regulates [...] Read more.
Extracellular vesicles (EVs) mediate cell-to-cell communication via the transfer of biomolecules locally and systemically between organs. It has been elucidated that the specific EV cargo load is fundamental for cellular response upon EV delivery. Therefore, revealing the specific molecular machinery that functionally regulates the precise EV cargo intracellularly is of importance in understanding the role of EVs in physiology and pathophysiology and conveying therapeutic use. The purpose of this review is to summarize recent findings on the general rules, as well as specific modulator motifs governing EV cargo loading. Finally, we address available information on potential therapeutic strategies to alter cargo loading. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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Review
Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance
Cells 2020, 9(6), 1450; https://doi.org/10.3390/cells9061450 - 11 Jun 2020
Cited by 26 | Viewed by 2777
Abstract
Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key [...] Read more.
Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biogenesis, Cargo and Disease)
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