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Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 80715

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A printed edition of this Special Issue is available here.

Special Issue Editor

Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
Interests: cancer biomarker; evidence-based medicine; extracellular vesicles; genomics; microRNA; molecular diagnostics; non-coding RNAs; nasopharyngeal carcinoma; next-generation sequencing; non-small cell lung cancer; proteomics; drug repurposing and bioinformatics
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Special Issue Information

Dear Colleagues,

In contrast to the artificial vehicles for drug delivery in cancer, extracellular vesicle (EV) as intercellular communication has attracted tremendous interest from the scientific community for use as a vehicle for therapeutics. EVs have been studied as delivery vehicles to transport drugs, proteins, and non-coding RNA for therapeutic purposes. Various approaches are emerging, with interesting experimental results.

The efficiency and specificity of drug delivery should be considered for targeting specific cell populations in dealing with tumor heterogeneity. EVs can be engineered to deliver specific bioactive molecules to target cells. The exploitation of their molecular composition and physical properties, as well as the use of bio-techniques to modify their content, are important issues to target them to specific cells/tissues/organs.

This Special Issue particularly focuses on how EVs offer a solution to molecular cancer therapeutics, thereby providing an efficient and effective way to treat cancer that marks a paradigm shift in modern oncology.

Original papers and review articles that focus on the latest advances of EVs are welcome. Papers and review articles on but not restricted to the following key areas will be covered:

  • Biology of EVs from various sources, e.g., platelet EVs, autologous cancer cell-derived EVs, etc.;
  • Red blood cell EVs as RNA-based therapeutics;
  • Mesenchymal stem cell-derived EVs as therapeutics and drug delivery platforms;
  • Macrophage-derived exosome–mimetic hybrid vesicles for targeted drug delivery in cancer;
  • Strategies in drug delivery by EVs, e.g., the modification of EV membranes;
  • Cancer EVs and their association with the microenvironment, including cancer-associated fibroblasts;
  • Clinical requirements for EV as a vehicle for cancer therapeutics;
  • EV-based therapeutics: natural versus engineered targeting;
  • EV-based therapeutics: safety and toxicity.

Dr. William Cho
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • extracellular vesicle
  • precision oncology
  • cancer biomarker
  • non-coding RNA
  • molecular diagnostics
  • genomics
  • proteomics

Published Papers (20 papers)

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Editorial

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5 pages, 180 KiB  
Editorial
Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics
by William C. S. Cho
Int. J. Mol. Sci. 2021, 22(17), 9586; https://doi.org/10.3390/ijms22179586 - 03 Sep 2021
Cited by 3 | Viewed by 1342
Abstract
Background [...] Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)

Research

Jump to: Editorial, Review

22 pages, 10819 KiB  
Article
Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles
by Agnieszka Szyposzynska, Aleksandra Bielawska-Pohl, Agnieszka Krawczenko, Olga Doszyn, Maria Paprocka and Aleksandra Klimczak
Int. J. Mol. Sci. 2020, 21(23), 9143; https://doi.org/10.3390/ijms21239143 - 30 Nov 2020
Cited by 10 | Viewed by 2320
Abstract
Transport of bioactive cargo of microvesicles (MVs) into target cells can affect their fate and behavior and change their microenvironment. We assessed the effect of MVs derived from human immortalized mesenchymal stem cells of adipose tissue-origin (HATMSC2-MVs) on the biological activity of the [...] Read more.
Transport of bioactive cargo of microvesicles (MVs) into target cells can affect their fate and behavior and change their microenvironment. We assessed the effect of MVs derived from human immortalized mesenchymal stem cells of adipose tissue-origin (HATMSC2-MVs) on the biological activity of the ovarian cancer cell lines ES-2 (clear cell carcinoma) and OAW-42 (cystadenocarcinoma). The HATMSC2-MVs were characterized using dynamic light scattering (DLS), transmission electron microscopy, and flow cytometry. The anti-tumor properties of HATMSC2-MVs were assessed using MTT for metabolic activity and flow cytometry for cell survival, cell cycle progression, and phenotype. The secretion profile of ovarian cancer cells was evaluated with a protein antibody array. Both cell lines internalized HATMSC2-MVs, which was associated with a decreased metabolic activity of cancer cells. HATMSC2-MVs exerted a pro-apoptotic and/or necrotic effect on ES-2 and OAW-42 cells and increased the expression of anti-tumor factors in both cell lines compared to control. In conclusion, we confirmed an effective transfer of HATMSC2-MVs into ovarian cancer cells that resulted in the inhibition of cell proliferation via different pathways, apoptosis and/or necrosis, which, with high likelihood, is related to the presence of different anti-tumor factors secreted by the ES-2 and OAW-42 cells. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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23 pages, 9416 KiB  
Article
Large Extracellular Vesicles Can be Characterised by Multiplex Labelling Using Imaging Flow Cytometry
by Suzanne M Johnson, Antonia Banyard, Christopher Smith, Aleksandr Mironov and Martin G. McCabe
Int. J. Mol. Sci. 2020, 21(22), 8723; https://doi.org/10.3390/ijms21228723 - 18 Nov 2020
Cited by 13 | Viewed by 3194
Abstract
Extracellular vesicles (EVs) are heterogeneous in size (30 nm–10 µm), content (lipid, RNA, DNA, protein), and potential function(s). Many isolation techniques routinely discard the large EVs at the early stages of small EV or exosome isolation protocols. We describe here a standardised method [...] Read more.
Extracellular vesicles (EVs) are heterogeneous in size (30 nm–10 µm), content (lipid, RNA, DNA, protein), and potential function(s). Many isolation techniques routinely discard the large EVs at the early stages of small EV or exosome isolation protocols. We describe here a standardised method to isolate large EVs from medulloblastoma cells and examine EV marker expression and diameter using imaging flow cytometry. Our approach permits the characterisation of each large EVs as an individual event, decorated with multiple fluorescently conjugated markers with the added advantage of visualising each event to ensure robust gating strategies are applied. Methods: We describe step-wise isolation and characterisation of a subset of large EVs from the medulloblastoma cell line UW228-2 assessed by fluorescent light microscopy, transmission electron microscopy (TEM) and tunable resistance pulse sensing (TRPS). Viability of parent cells was assessed by Annexin V exposure by flow cytometry. Imaging flow cytometry (Imagestream Mark II) identified EVs by direct fluorescent membrane labelling with Cell Mask Orange (CMO) in conjunction with EV markers. A stringent gating algorithm based on side scatter and fluorescence intensity was applied and expression of EV markers CD63, CD9 and LAMP 1 assessed. Results: UW228-2 cells prolifically release EVs of up to 6 µm. We show that the Imagestream Mark II imaging flow cytometer allows robust and reproducible analysis of large EVs, including assessment of diameter. We also demonstrate a correlation between increasing EV size and co-expression of markers screened. Conclusions: We have developed a labelling and stringent gating strategy which is able to explore EV marker expression (CD63, CD9, and LAMP1) on individual EVs within a widely heterogeneous population. Taken together, data presented here strongly support the value of exploring large EVs in clinical samples for potential biomarkers, useful in diagnostic screening and disease monitoring. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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25 pages, 5189 KiB  
Article
Phenotypic and Functional Characteristics of Exosomes Derived from Irradiated Mouse Organs and Their Role in the Mechanisms Driving Non-Targeted Effects
by Seda Tuncay Cagatay, Ammar Mayah, Mariateresa Mancuso, Paola Giardullo, Simonetta Pazzaglia, Anna Saran, Amuthachelvi Daniel, Damien Traynor, Aidan D. Meade, Fiona Lyng, Soile Tapio and Munira Kadhim
Int. J. Mol. Sci. 2020, 21(21), 8389; https://doi.org/10.3390/ijms21218389 - 09 Nov 2020
Cited by 27 | Viewed by 3435
Abstract
Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators [...] Read more.
Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators of NTE. Although exosome-mediated changes are well documented in radiation therapy and oncology, there is a lack of knowledge regarding the role of exosomes derived from inside and outside the radiation field in the early and delayed induction of NTE following IR. Therefore, here we investigated the changes in exosome profile and the role of exosomes as possible molecular signalling mediators of radiation damage. Exosomes derived from organs of whole body irradiated (WBI) or partial body irradiated (PBI) mice after 24 h and 15 days post-irradiation were transferred to recipient mouse embryonic fibroblast (MEF) cells and changes in cellular viability, DNA damage and calcium, reactive oxygen species and nitric oxide signalling were evaluated compared to that of MEF cells treated with exosomes derived from unirradiated mice. Taken together, our results show that whole and partial-body irradiation increases the number of exosomes, instigating changes in exosome-treated MEF cells, depending on the source organ and time after exposure. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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15 pages, 16261 KiB  
Article
Analysis of Serum miRNA in Glioblastoma Patients: CD44-Based Enrichment of Extracellular Vesicles Enhances Specificity for the Prognostic Signature
by Theophilos Tzaridis, Katrin S Reiners, Johannes Weller, Daniel Bachurski, Niklas Schäfer, Christina Schaub, Michael Hallek, Björn Scheffler, Martin Glas, Ulrich Herrlinger, Stefan Wild, Christoph Coch and Gunther Hartmann
Int. J. Mol. Sci. 2020, 21(19), 7211; https://doi.org/10.3390/ijms21197211 - 29 Sep 2020
Cited by 17 | Viewed by 3051
Abstract
Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EVs) from the serum of glioblastoma patients [...] Read more.
Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EVs) from the serum of glioblastoma patients and evaluated their correlation with the prognosis of these patients. The levels of 15 microRNAs in EVs that were separated by size-exclusion chromatography were studied by quantitative real-time PCR, followed by CD44 immunoprecipitation (SEC + CD44), and compared with those from the total serum of glioblastoma patients (n = 55) and healthy volunteers (n = 10). Compared to total serum, we found evidence for the enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p, in SEC + CD44 EVs. miR-15b-3p and miR-21-3p were upregulated in glioblastoma patients compared to healthy subjects. A significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p, and miR-328-3p in SEC + CD44 EVs. Combining miR-15b-3p in serum or miR-106a-5p in SEC + CD44 EVs with any one of the other three microRNAs in SEC + CD44 EVs allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs in glioblastoma patients whose levels, in combination, can predict the prognosis for these patients. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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15 pages, 2032 KiB  
Article
Measuring Extracellular Vesicles by Conventional Flow Cytometry: Dream or Reality?
by Donatella Lucchetti, Alessandra Battaglia, Claudio Ricciardi-Tenore, Filomena Colella, Luigi Perelli, Ruggero De Maria, Giovanni Scambia, Alessandro Sgambato and Andrea Fattorossi
Int. J. Mol. Sci. 2020, 21(17), 6257; https://doi.org/10.3390/ijms21176257 - 29 Aug 2020
Cited by 18 | Viewed by 4235
Abstract
Intense research is being conducted using flow cytometers available in clinically oriented laboratories to assess extracellular vesicles (EVs) surface cargo in a variety of diseases. Using EVs of various sizes purified from the HT29 human colorectal adenocarcinoma cell line, we report on the [...] Read more.
Intense research is being conducted using flow cytometers available in clinically oriented laboratories to assess extracellular vesicles (EVs) surface cargo in a variety of diseases. Using EVs of various sizes purified from the HT29 human colorectal adenocarcinoma cell line, we report on the difficulty to assess small and medium sized EVs by conventional flow cytometer that combines light side scatter off a 405 nm laser with the fluorescent signal from the EVs general labels Calcein-green and Calcein-violet, and surface markers. Small sized EVs (~70 nm) immunophenotyping failed, consistent with the scarcity of monoclonal antibody binding sites, and were therefore excluded from further investigation. Medium sized EVs (~250 nm) immunophenotyping was possible but their detection was plagued by an excess of coincident particles (swarm detection) and by a high abort rate; both factors affected the measured EVs concentration. By running samples containing equal amounts of Calcein-green and Calcein-violet stained medium sized EVs, we found that swarm detection produced false double positive events, a phenomenon that was significantly reduced, but not totally eliminated, by sample dilution. Moreover, running highly diluted samples required long periods of cytometer time. Present findings raise questions about the routine applicability of conventional flow cytometers for EV analysis. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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16 pages, 4597 KiB  
Article
Optimized Protocol for Isolation of Small Extracellular Vesicles from Human and Murine Lymphoid Tissues
by Marie Bordas, Géraldine Genard, Sibylle Ohl, Michelle Nessling, Karsten Richter, Tobias Roider, Sascha Dietrich, Kendra K. Maaß and Martina Seiffert
Int. J. Mol. Sci. 2020, 21(15), 5586; https://doi.org/10.3390/ijms21155586 - 04 Aug 2020
Cited by 15 | Viewed by 4272
Abstract
Small extracellular vesicles (sEVs) are nanoparticles responsible for cell-to-cell communication released by healthy and cancer cells. Different roles have been described for sEVs in physiological and pathological contexts, including acceleration of tissue regeneration, modulation of tumor microenvironment, or premetastatic niche formation, and they [...] Read more.
Small extracellular vesicles (sEVs) are nanoparticles responsible for cell-to-cell communication released by healthy and cancer cells. Different roles have been described for sEVs in physiological and pathological contexts, including acceleration of tissue regeneration, modulation of tumor microenvironment, or premetastatic niche formation, and they are discussed as promising biomarkers for diagnosis and prognosis in body fluids. Although efforts have been made to standardize techniques for isolation and characterization of sEVs, current protocols often result in co-isolation of soluble protein or lipid complexes and of other extracellular vesicles. The risk of contaminated preparations is particularly high when isolating sEVs from tissues. As a consequence, the interpretation of data aiming at understanding the functional role of sEVs remains challenging and inconsistent. Here, we report an optimized protocol for isolation of sEVs from human and murine lymphoid tissues. sEVs from freshly resected human lymph nodes and murine spleens were isolated comparing two different approaches—(1) ultracentrifugation on a sucrose density cushion and (2) combined ultracentrifugation with size-exclusion chromatography. The purity of sEV preparations was analyzed using state-of-the-art techniques, including immunoblots, nanoparticle tracking analysis, and electron microscopy. Our results clearly demonstrate the superiority of size-exclusion chromatography, which resulted in a higher yield and purity of sEVs, and we show that their functionality alters significantly between the two isolation protocols. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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20 pages, 3179 KiB  
Article
Small Extracellular Vesicles Isolated from Serum May Serve as Signal-Enhancers for the Monitoring of CNS Tumors
by Gabriella Dobra, Matyas Bukva, Zoltan Szabo, Bella Bruszel, Maria Harmati, Edina Gyukity-Sebestyen, Adrienn Jenei, Monika Szucs, Peter Horvath, Tamas Biro, Almos Klekner and Krisztina Buzas
Int. J. Mol. Sci. 2020, 21(15), 5359; https://doi.org/10.3390/ijms21155359 - 28 Jul 2020
Cited by 20 | Viewed by 4206
Abstract
Liquid biopsy-based methods to test biomarkers (e.g., serum proteins and extracellular vesicles) may help to monitor brain tumors. In this proteomics-based study, we aimed to identify a characteristic protein fingerprint associated with central nervous system (CNS) tumors. Overall, 96 human serum samples were [...] Read more.
Liquid biopsy-based methods to test biomarkers (e.g., serum proteins and extracellular vesicles) may help to monitor brain tumors. In this proteomics-based study, we aimed to identify a characteristic protein fingerprint associated with central nervous system (CNS) tumors. Overall, 96 human serum samples were obtained from four patient groups, namely glioblastoma multiforme (GBM), non-small-cell lung cancer brain metastasis (BM), meningioma (M) and lumbar disc hernia patients (CTRL). After the isolation and characterization of small extracellular vesicles (sEVs) by nanoparticle tracking analysis (NTA) and atomic force microscopy (AFM), liquid chromatography -mass spectrometry (LC-MS) was performed on two different sample types (whole serum and serum sEVs). Statistical analyses (ratio, Cohen’s d, receiver operating characteristic; ROC) were carried out to compare patient groups. To recognize differences between the two sample types, pairwise comparisons (Welch’s test) and ingenuity pathway analysis (IPA) were performed. According to our knowledge, this is the first study that compares the proteome of whole serum and serum-derived sEVs. From the 311 proteins identified, 10 whole serum proteins and 17 sEV proteins showed the highest intergroup differences. Sixty-five proteins were significantly enriched in sEV samples, while 129 proteins were significantly depleted compared to whole serum. Based on principal component analysis (PCA) analyses, sEVs are more suitable to discriminate between the patient groups. Our results support that sEVs have greater potential to monitor CNS tumors, than whole serum. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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10 pages, 2225 KiB  
Communication
Three Method-Combination Protocol for Improving Purity of Extracellular Vesicles
by Thomas Simon, Anish Kumaran, Diana-Florentina Veselu and Georgios Giamas
Int. J. Mol. Sci. 2020, 21(9), 3071; https://doi.org/10.3390/ijms21093071 - 27 Apr 2020
Cited by 10 | Viewed by 4940
Abstract
Extracellular vesicles (EVs) are nanosized structures able to carry proteins, lipids and genetic material from one cell to another with critical implications in intercellular communication mechanisms. Even though the rapidly growing EVs research field has sparked great interest in the last 20 years, [...] Read more.
Extracellular vesicles (EVs) are nanosized structures able to carry proteins, lipids and genetic material from one cell to another with critical implications in intercellular communication mechanisms. Even though the rapidly growing EVs research field has sparked great interest in the last 20 years, many biological and technical aspects still remain challenging. One of the main issues that the field is facing is the absence of consensus regarding methods for EVs concentration from biofluids and tissue culture medium. Yet, not only can classic methods be time consuming, commercialized kits are also often quite expensive, especially when research requires analyzing numerous samples or concentrating EVs from large sample volumes. In addition, EV concentration often results in either low final yield or significant contamination of the vesicle sample with proteins and protein complexes of similar densities and sizes. Eventually, low vesicle yields highly limit any further application and data reproducibility while contamination greatly impacts extensive functional studies. Hence, there is a need for accessible and sustainable methods for improved vesicle concentration as this is a critical step in any EVs-related research study. In this brief report, we describe a novel combination of three well-known methods in order to obtain moderate-to-high yields of EVs with reduced protein contamination. We believe that such methods could be of high benefits for in vitro and in vivo functional studies. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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16 pages, 3734 KiB  
Article
Potential Use of Extracellular Vesicles Generated by Microbubble-Assisted Ultrasound as Drug Nanocarriers for Cancer Treatment
by Yuana Yuana, Banuja Balachandran, Kim M. G. van der Wurff-Jacobs, Raymond M. Schiffelers and Chrit T. Moonen
Int. J. Mol. Sci. 2020, 21(8), 3024; https://doi.org/10.3390/ijms21083024 - 24 Apr 2020
Cited by 14 | Viewed by 3819
Abstract
Extracellular vesicles (EVs)-carrying biomolecules derived from parental cells have achieved substantial scientific interest for their potential use as drug nanocarriers. Ultrasound (US) in combination with microbubbles (MB) have been shown to trigger the release of EVs from cancer cells. In the current study, [...] Read more.
Extracellular vesicles (EVs)-carrying biomolecules derived from parental cells have achieved substantial scientific interest for their potential use as drug nanocarriers. Ultrasound (US) in combination with microbubbles (MB) have been shown to trigger the release of EVs from cancer cells. In the current study, the use of microbubbles-assisted ultrasound (USMB) to generate EVs containing drug cargo was investigated. The model drug, CellTracker™ green fluorescent dye (CTG) or bovine serum albumin conjugated with fluorescein isothiocyanate (BSA FITC) was loaded into primary human endothelial cells in vitro using USMB. We found that USMB loaded CTG and BSA FITC into human endothelial cells (HUVECs) and triggered the release of EVs containing these compounds in the cell supernatant within 2 h after treatment. The amount of EV released seemed to be correlated with the increase of US acoustic pressure. Co-culturing these EVs resulted in uptake by the recipient tumour cells within 4 h. In conclusion, USMB was able to load the model drugs into endothelial cells and simultaneously trigger the release of EVs-carrying model drugs, highlighting the potential of EVs as drug nanocarriers for future drug delivery in cancer. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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Review

Jump to: Editorial, Research

27 pages, 2441 KiB  
Review
Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer
by Ancuta Jurj, Cecilia Pop-Bica, Ondrej Slaby, Cristina D. Ştefan, William C. Cho, Schuyler S. Korban and Ioana Berindan-Neagoe
Int. J. Mol. Sci. 2020, 21(20), 7688; https://doi.org/10.3390/ijms21207688 - 17 Oct 2020
Cited by 12 | Viewed by 2587
Abstract
Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management [...] Read more.
Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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23 pages, 2373 KiB  
Review
The Biological Function and Therapeutic Potential of Exosomes in Cancer: Exosomes as Efficient Nanocommunicators for Cancer Therapy
by Jeong Uk Choi, In-Kyu Park, Yong-Kyu Lee and Seung Rim Hwang
Int. J. Mol. Sci. 2020, 21(19), 7363; https://doi.org/10.3390/ijms21197363 - 05 Oct 2020
Cited by 18 | Viewed by 4217
Abstract
Cancer therapeutics must be delivered to their targets for improving efficacy and reducing toxicity, though they encounter physiological barriers in the tumor microenvironment. They also face limitations associated with genetic instability and dynamic changes of surface proteins in cancer cells. Nanosized exosomes generated [...] Read more.
Cancer therapeutics must be delivered to their targets for improving efficacy and reducing toxicity, though they encounter physiological barriers in the tumor microenvironment. They also face limitations associated with genetic instability and dynamic changes of surface proteins in cancer cells. Nanosized exosomes generated from the endosomal compartment, however, transfer their cargo to the recipient cells and mediate the intercellular communication, which affects malignancy progression, tumor immunity, and chemoresistance. In this review, we give an overview of exosomes’ biological aspects and therapeutic potential as diagnostic biomarkers and drug delivery vehicles for oncotherapy. Furthermore, we discuss whether exosomes could contribute to personalized cancer immunotherapy drug design as efficient nanocommunicators. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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17 pages, 351 KiB  
Review
More than Nutrition: Therapeutic Potential of Breast Milk-Derived Exosomes in Cancer
by Ki-Uk Kim, Wan-Hoon Kim, Chi Hwan Jeong, Dae Yong Yi and Hyeyoung Min
Int. J. Mol. Sci. 2020, 21(19), 7327; https://doi.org/10.3390/ijms21197327 - 03 Oct 2020
Cited by 44 | Viewed by 5789
Abstract
Human breast milk (HBM) is an irreplaceable source of nutrition for early infant growth and development. Breast-fed children are known to have a low prevalence and reduced risk of various diseases, such as necrotizing enterocolitis, gastroenteritis, acute lymphocytic leukemia, and acute myeloid leukemia. [...] Read more.
Human breast milk (HBM) is an irreplaceable source of nutrition for early infant growth and development. Breast-fed children are known to have a low prevalence and reduced risk of various diseases, such as necrotizing enterocolitis, gastroenteritis, acute lymphocytic leukemia, and acute myeloid leukemia. In recent years, HBM has been found to contain a microbiome, extracellular vesicles or exosomes, and microRNAs, as well as nutritional components and non-nutritional proteins, including immunoregulatory proteins, hormones, and growth factors. Especially, the milk-derived exosomes exert various physiological and therapeutic function in cell proliferation, inflammation, immunomodulation, and cancer, which are mainly attributed to their cargo molecules such as proteins and microRNAs. The exosomal miRNAs are protected from enzymatic digestion and acidic conditions, and play a critical role in immune regulation and cancer. In addition, the milk-derived exosomes are developed as drug carriers for delivering small molecules and siRNA to tumor sites. In this review, we examined the various components of HBM and their therapeutic potential, in particular of exosomes and microRNAs, towards cancer. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
20 pages, 2329 KiB  
Review
Exploiting Manipulated Small Extracellular Vesicles to Subvert Immunosuppression at the Tumor Microenvironment through Mannose Receptor/CD206 Targeting
by Maria Luisa Fiani, Valeria Barreca, Massimo Sargiacomo, Flavia Ferrantelli, Francesco Manfredi and Maurizio Federico
Int. J. Mol. Sci. 2020, 21(17), 6318; https://doi.org/10.3390/ijms21176318 - 31 Aug 2020
Cited by 15 | Viewed by 4559
Abstract
Immunosuppression at tumor microenvironment (TME) is one of the major obstacles to be overcome for an effective therapeutic intervention against solid tumors. Tumor-associated macrophages (TAMs) comprise a sub-population that plays multiple pro-tumoral roles in tumor development including general immunosuppression, which can be identified [...] Read more.
Immunosuppression at tumor microenvironment (TME) is one of the major obstacles to be overcome for an effective therapeutic intervention against solid tumors. Tumor-associated macrophages (TAMs) comprise a sub-population that plays multiple pro-tumoral roles in tumor development including general immunosuppression, which can be identified in terms of high expression of mannose receptor (MR or CD206). Immunosuppressive TAMs, like other macrophage sub-populations, display functional plasticity that allows them to be re-programmed to inflammatory macrophages. In order to mitigate immunosuppression at the TME, several efforts are ongoing to effectively re-educate pro-tumoral TAMs. Extracellular vesicles (EVs), released by both normal and tumor cells types, are emerging as key mediators of the cell to cell communication and have been shown to have a role in the modulation of immune responses in the TME. Recent studies demonstrated the enrichment of high mannose glycans on the surface of small EVs (sEVs), a subtype of EVs of endosomal origin of 30–150 nm in diameter. This characteristic renders sEVs an ideal tool for the delivery of therapeutic molecules into MR/CD206-expressing TAMs. In this review, we report the most recent literature data highlighting the critical role of TAMs in tumor development, as well as the experimental evidences that has emerged from the biochemical characterization of sEV membranes. In addition, we propose an original way to target immunosuppressive TAMs at the TME by endogenously engineered sEVs for a new therapeutic approach against solid tumors. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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22 pages, 617 KiB  
Review
Extracellular Vesicles in the Development of Cancer Therapeutics
by Haoyao Sun, Stephanie Burrola, Jinchang Wu and Wei-Qun Ding
Int. J. Mol. Sci. 2020, 21(17), 6097; https://doi.org/10.3390/ijms21176097 - 24 Aug 2020
Cited by 41 | Viewed by 4438
Abstract
Extracellular vesicles (EVs) are small lipid bilayer-delimited nanoparticles released from all types of cells examined thus far. Several groups of EVs, including exosomes, microvesicles, and apoptotic bodies, have been identified according to their size and biogenesis. With extensive investigations on EVs over the [...] Read more.
Extracellular vesicles (EVs) are small lipid bilayer-delimited nanoparticles released from all types of cells examined thus far. Several groups of EVs, including exosomes, microvesicles, and apoptotic bodies, have been identified according to their size and biogenesis. With extensive investigations on EVs over the last decade, it is now recognized that EVs play a pleiotropic role in various physiological processes as well as pathological conditions through mediating intercellular communication. Most notably, EVs have been shown to be involved in cancer initiation and progression and EV signaling in cancer are viewed as potential therapeutic targets. Furthermore, as membrane nanoparticles, EVs are natural products with some of them, such as tumor exosomes, possessing tumor homing propensity, thus leading to strategies utilizing EVs as drug carriers to effectively deliver cancer therapeutics. In this review, we summarize recent reports on exploring EVs signaling as potential therapeutic targets in cancer as well as on developing EVs as therapeutic delivery carriers for cancer therapy. Findings from preclinical studies are primarily discussed, with early phase clinical trials reviewed. We hope to provide readers updated information on the development of EVs as cancer therapeutic targets or therapeutic carriers. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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30 pages, 1430 KiB  
Review
Microvesicles in Cancer: Small Size, Large Potential
by Kerstin Menck, Suganja Sivaloganathan, Annalen Bleckmann and Claudia Binder
Int. J. Mol. Sci. 2020, 21(15), 5373; https://doi.org/10.3390/ijms21155373 - 28 Jul 2020
Cited by 43 | Viewed by 4857
Abstract
Extracellular vesicles (EV) are secreted by all cell types in a tumor and its microenvironment (TME), playing an essential role in intercellular communication and the establishment of a TME favorable for tumor invasion and metastasis. They encompass a variety of vesicle populations, among [...] Read more.
Extracellular vesicles (EV) are secreted by all cell types in a tumor and its microenvironment (TME), playing an essential role in intercellular communication and the establishment of a TME favorable for tumor invasion and metastasis. They encompass a variety of vesicle populations, among them the well-known endosomal-derived small exosomes (Exo), but also larger vesicles (diameter > 100 nm) that are shed directly from the plasma membrane, the so-called microvesicles (MV). Increasing evidence suggests that MV, although biologically different, share the tumor-promoting features of Exo in the TME. Due to their larger size, they can be readily harvested from patients’ blood and characterized by routine methods such as conventional flow cytometry, exploiting the plethora of molecules expressed on their surface. In this review, we summarize the current knowledge about the biology and the composition of MV, as well as their role within the TME. We highlight not only the challenges and potential of MV as novel biomarkers for cancer, but also discuss their possible use for therapeutic intervention. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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18 pages, 596 KiB  
Review
Platelets Extracellular Vesicles as Regulators of Cancer Progression—An Updated Perspective
by Magdalena Żmigrodzka, Olga Witkowska-Piłaszewicz and Anna Winnicka
Int. J. Mol. Sci. 2020, 21(15), 5195; https://doi.org/10.3390/ijms21155195 - 22 Jul 2020
Cited by 36 | Viewed by 3727
Abstract
Extracellular vesicles (EVs) are a diverse group of membrane-bound structures secreted in physiological and pathological conditions by prokaryotic and eukaryotic cells. Their role in cell-to-cell communications has been discussed for more than two decades. More attention is paid to assess the impact of [...] Read more.
Extracellular vesicles (EVs) are a diverse group of membrane-bound structures secreted in physiological and pathological conditions by prokaryotic and eukaryotic cells. Their role in cell-to-cell communications has been discussed for more than two decades. More attention is paid to assess the impact of EVs in cancer. Numerous papers showed EVs as tumorigenesis regulators, by transferring their cargo molecules (miRNA, DNA, protein, cytokines, receptors, etc.) among cancer cells and cells in the tumor microenvironment. During platelet activation or apoptosis, platelet extracellular vesicles (PEVs) are formed. PEVs present a highly heterogeneous EVs population and are the most abundant EVs group in the circulatory system. The reason for the PEVs heterogeneity are their maternal activators, which is reflected on PEVs size and cargo. As PLTs role in cancer development is well-known, and PEVs are the most numerous EVs in blood, their feasible impact on cancer growth is strongly discussed. PEVs crosstalk could promote proliferation, change tumor microenvironment, favor metastasis formation. In many cases these functions were linked to the transfer into recipient cells specific cargo molecules from PEVs. The article reviews the PEVs biogenesis, cargo molecules, and their impact on the cancer progression. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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21 pages, 1210 KiB  
Review
Signaling of Tumor-Derived sEV Impacts Melanoma Progression
by Aneta Zebrowska, Piotr Widlak, Theresa Whiteside and Monika Pietrowska
Int. J. Mol. Sci. 2020, 21(14), 5066; https://doi.org/10.3390/ijms21145066 - 17 Jul 2020
Cited by 23 | Viewed by 3346
Abstract
Small extracellular vesicles (sEV or exosomes) are nanovesicles (30–150 nm) released both in vivo and in vitro by most cell types. Tumor cells produce sEV called TEX and disperse them throughout all body fluids. TEX contain a cargo of proteins, lipids, and RNA [...] Read more.
Small extracellular vesicles (sEV or exosomes) are nanovesicles (30–150 nm) released both in vivo and in vitro by most cell types. Tumor cells produce sEV called TEX and disperse them throughout all body fluids. TEX contain a cargo of proteins, lipids, and RNA that is similar but not identical to that of the “parent” producer cell (i.e., the cargo of exosomes released by melanoma cells is similar but not identical to exosomes released by melanocytes), possibly due to selective endosomal packaging. TEX and their role in cancer biology have been intensively investigated largely due to the possibility that TEX might serve as key component of a “liquid tumor biopsy.” TEX are also involved in the crosstalk between cancer and immune cells and play a key role in the suppression of anti-tumor immune responses, thus contributing to the tumor progression. Most of the available information about the TEX molecular composition and functions has been gained using sEV isolated from supernatants of cancer cell lines. However, newer data linking plasma levels of TEX with cancer progression have focused attention on TEX in the patients’ peripheral circulation as potential biomarkers of cancer diagnosis, development, activity, and response to therapy. Here, we consider the molecular cargo and functions of TEX as potential biomarkers of one of the most fatal malignancies—melanoma. Studies of TEX in plasma of patients with melanoma offer the possibility of an in-depth understanding of the melanoma biology and response to immune therapies. This review features melanoma cell-derived exosomes (MTEX) with special emphasis on exosome-mediated signaling between melanoma cells and the host immune system. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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18 pages, 1778 KiB  
Review
Diagnostic and Therapeutic Applications of Exosomes in Cancer with a Special Focus on Head and Neck Squamous Cell Carcinoma (HNSCC)
by Eliane Ebnoether and Laurent Muller
Int. J. Mol. Sci. 2020, 21(12), 4344; https://doi.org/10.3390/ijms21124344 - 18 Jun 2020
Cited by 17 | Viewed by 3123
Abstract
Exosomes are nanovesicles part of a recently described intercellular communication system. Their properties seem promising as a biomarker in cancer research, where more sensitive monitoring and therapeutic applications are desperately needed. In the case of head and neck squamous cell carcinoma (HNSCC), overall [...] Read more.
Exosomes are nanovesicles part of a recently described intercellular communication system. Their properties seem promising as a biomarker in cancer research, where more sensitive monitoring and therapeutic applications are desperately needed. In the case of head and neck squamous cell carcinoma (HNSCC), overall survival often remains poor, although huge technological advancements in the treatment of this disease have been made. In the following review, diagnostic and therapeutic properties are highlighted and summarised. Impressive first results have been obtained but more research is needed to implement these innovative techniques into daily clinical routines. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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14 pages, 1981 KiB  
Review
Exosomes in Prostate Cancer Diagnosis, Prognosis and Therapy
by Tomasz Lorenc, Katarzyna Klimczyk, Izabela Michalczewska, Monika Słomka, Grażyna Kubiak-Tomaszewska and Wioletta Olejarz
Int. J. Mol. Sci. 2020, 21(6), 2118; https://doi.org/10.3390/ijms21062118 - 19 Mar 2020
Cited by 79 | Viewed by 7912
Abstract
Prostate cancer (PCa) is the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of [...] Read more.
Prostate cancer (PCa) is the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. Exosomes are involved in tumor progression, promoting the angiogenesis and migration of tumor cells during metastasis. These structures contribute to the dissemination of pathogenic agents through interaction with recipient cells. Exosomes may deliver molecules that are able to induce the transdifferentiation process, known as “epithelial to mesenchymal transition”. The composition of exosomes and the associated possibilities of interacting with cells make exosomes multifaceted regulators of cancer development. Extracellular vesicles have biophysical properties, such as stability, biocompatibility, permeability, low toxicity and low immunogenicity, which are key for the successful development of an innovative drug delivery system. They have an enhanced circulation stability and bio-barrier permeation ability, and they can therefore be used as effective chemotherapeutic carriers to improve the regulation of target tissues and organs. Exosomes have the capacity to deliver different types of cargo and to target specific cells. Chemotherapeutics, natural products and RNA have been encapsulated for the treatment of prostate cancers. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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