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Biomedicines
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Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management
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Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 16236

Special Issue Editors

Dr. Igea D'Agnano

E-Mail Website
Guest Editor
Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, Milan, Italy
Interests: human malignant glioma; preclinical tumor models; circulating miRNAs; liquid biopsy; EV diagnostics; EV characterisation; EV heterogeneity; EV flow cytometry; EV-contained miRNAs
Special Issues, Collections and Topics in MDPI journals
Dr. Ingrid Cifola

E-Mail Website
Guest Editor
Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, Milan, Italy
Interests: cancer genomics; translational medicine; next-generation sequencing; bioinformatics; single-cell sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is quite ascertained that extracellular vesicles (EVs) mediate cell-to-cell communication in cancer. Tumor cells produce large amounts of EVs, whose cargo is composed by nucleic acids, proteins and lipids that are delivered to nearby or distant recipient cells. Cells are able to select the EV cargo, thus safeguarding the molecules packaged into the EVs from enzymatic degradation. It has been found also that EVs are involved in the cell cross-talk within the tumour microenvironment and crucially influence several cancer-associated features, such as the immune recognition of malignant cells, the vascular permeability, the extracellular matrix remodelling, the establishment of an inflammatory state, and the formation of metastatic niche.

In the brain, EVs are secreted by not only tumor cells, but also all the other existing cell types, such as astrocytes, oligodendrocytes, microglia and neurons. Recent studies reveal that miRNAs are secreted in the body fluids as EV cargo and are able to influence the recipient cell phenotype. EVs properly function as reservoir for miRNAs, which thanks to their safeguard remain stable and easily accessible, and can properly reflect the pathophysiological state of the primary affected tissue. For these reasons and also because EVs are secreted with a distinctive composition by all cell types in all body fluids, miRNA contained in EVs are promising candidate liquid biomarkers of great significance for cancer. In this scenario, the isolation of miRNAs from EVs to identify molecular signatures for brain tumor early diagnosis could possibly replace the more costly and invasive tissue biopsy procedures in the near future.

In addition, the ability of EVs to act as natural carriers offers a novel platform for the development of new therapeutic strategies. However, in spite of these prospects, many EV-related aspects such as EV production, isolation and cargo definition as well as their role in cancer progression and subsequent theranostic applications still remain to be fully defined.

The purpose of this Special Issue is to attract articles (both original research articles and reviews) from experts in the field of EV research in the brain tumor that can take innovative approaches or express novel views on the multifaceted world of EVs in cancer biology, progression and therapy. We invite the colleagues to focus on the small EVs, which has been widely demonstrated to mediate transfer of several bioactive molecules including miRNA.

Original papers and review articles that focus on the latest advances in small EV studies for brain tumor management are welcome.

Key areas that will be covered in this Special Issue include the following:

The use of model systems to study the biology of small EVs in brain tumors and their use for theranostic approaches;

The relations between the cells of origin and their targets;

The use of EVs as a source of candidate biomarkers for liquid biopsy;

The role of EVs in inflammation and shaping of the brain tumor microenvironment;

The characterization of specific cargos and their role in recipient cells and cancer progression;

The EV engineering for design of targeted therapy strategies.

Dr. Igea D'Agnano
Dr. Ingrid Cifola
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • extracellular vesicles
  • brain tumors
  • tumor microenvironment
  • liquid biopsy
  • tumor biomarkers
  • microRNAs
  • gene expression

Published Papers (7 papers)

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Research

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18 pages, 4969 KiB  
Article
Astrocytes-Derived Small Extracellular Vesicles Hinder Glioma Growth
by Carmela Serpe, Antonio Michelucci, Lucia Monaco, Arianna Rinaldi, Mariassunta De Luca, Pietro Familiari, Michela Relucenti, Erika Di Pietro, Maria Amalia Di Castro, Igea D’Agnano, Luigi Catacuzzeno, Cristina Limatola and Myriam Catalano
Biomedicines 2022, 10(11), 2952; https://doi.org/10.3390/biomedicines10112952 - 17 Nov 2022
Cited by 6 | Viewed by 1807
Abstract
All cells are capable of secreting extracellular vesicles (EVs), which are not a means to eliminate unneeded cellular compounds but represent a process to exchange material (nucleic acids, lipids and proteins) between different cells. This also happens in the brain, where EVs permit [...] Read more.
All cells are capable of secreting extracellular vesicles (EVs), which are not a means to eliminate unneeded cellular compounds but represent a process to exchange material (nucleic acids, lipids and proteins) between different cells. This also happens in the brain, where EVs permit the crosstalk between neuronal and non-neuronal cells, functional to homeostatic processes or cellular responses to pathological stimuli. In brain tumors, EVs are responsible for the bidirectional crosstalk between glioblastoma cells and healthy cells, and among them, astrocytes, that assume a pro-tumoral or antitumoral role depending on the stage of the tumor progression. In this work, we show that astrocyte-derived small EVs (sEVs) exert a defensive mechanism against tumor cell growth and invasion. The effect is mediated by astrocyte-derived EVs (ADEVs) through the transfer to tumor cells of factors that hinder glioma growth. We identified one of these factors, enriched in ADEVs, that is miR124. It reduced both the expression and function of the volume-regulated anion channel (VRAC), that, in turn, decreased the cell migration and invasion of murine glioma GL261 cells. Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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23 pages, 3155 KiB  
Article
miRNome and Proteome Profiling of Small Extracellular Vesicles Secreted by Human Glioblastoma Cell Lines and Primary Cancer Stem Cells
by Ingrid Cifola, Federica Fratini, Beatrice Cardinali, Valentina Palmieri, Giuliana Gatti, Tommaso Selmi, Sara Donzelli, Andrea Sacconi, Valeriana Cesarini, Hany E. Marei, Massimilano Papi, Giovanni Blandino, Carlo Cenciarelli, Germana Falcone and Igea D’Agnano
Biomedicines 2022, 10(8), 1886; https://doi.org/10.3390/biomedicines10081886 - 4 Aug 2022
Cited by 1 | Viewed by 2266
Abstract
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite available therapeutic interventions, it is very difficult to treat, and a cure is not yet available. The intra-tumoral GBM heterogeneity is a crucial factor contributing to poor clinical outcomes. GBM [...] Read more.
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite available therapeutic interventions, it is very difficult to treat, and a cure is not yet available. The intra-tumoral GBM heterogeneity is a crucial factor contributing to poor clinical outcomes. GBM derives from a small heterogeneous population of cancer stem cells (CSCs). In cancer tissue, CSCs are concentrated within the so-called niches, where they progress from a slowly proliferating phase. CSCs, as most tumor cells, release extracellular vesicles (EVs) into the surrounding microenvironment. To explore the role of EVs in CSCs and GBM tumor cells, we investigated the miRNA and protein content of the small EVs (sEVs) secreted by two GBM-established cell lines and by GBM primary CSCs using omics analysis. Our data indicate that GBM-sEVs are selectively enriched for miRNAs that are known to display tumor suppressor activity, while their protein cargo is enriched for oncoproteins and tumor-associated proteins. Conversely, among the most up-regulated miRNAs in CSC-sEVs, we also found pro-tumor miRNAs and proteins related to stemness, cell proliferation, and apoptosis. Collectively, our findings support the hypothesis that sEVs selectively incorporate different miRNAs and proteins belonging both to fundamental processes (e.g., cell proliferation, cell death, stemness) as well as to more specialized ones (e.g., EMT, membrane docking, cell junction organization, ncRNA processing). Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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15 pages, 1659 KiB  
Article
Extracellular Vesicles from Human Cerebrospinal Fluid Are Effectively Separated by Sepharose CL-6B—Comparison of Four Gravity-Flow Size Exclusion Chromatography Methods
by Vedrana Krušić Alić, Mladenka Malenica, Maša Biberić, Siniša Zrna, Lara Valenčić, Aleksandar Šuput, Lada Kalagac Fabris, Karmen Wechtersbach, Nika Kojc, Mario Kurtjak, Natalia Kučić and Kristina Grabušić
Biomedicines 2022, 10(4), 785; https://doi.org/10.3390/biomedicines10040785 - 27 Mar 2022
Cited by 15 | Viewed by 3397
Abstract
Extracellular vesicles (EVs) are a versatile group of cell-secreted membranous nanoparticles present in body fluids. They have an exceptional diagnostic potential due to their molecular content matching the originating cells and accessibility from body fluids. However, methods for EV isolation are still in [...] Read more.
Extracellular vesicles (EVs) are a versatile group of cell-secreted membranous nanoparticles present in body fluids. They have an exceptional diagnostic potential due to their molecular content matching the originating cells and accessibility from body fluids. However, methods for EV isolation are still in development, with size exclusion chromatography (SEC) emerging as a preferred method. Here we compared four types of SEC to isolate EVs from the CSF of patients with severe traumatic brain injury. A pool of nine CSF samples was separated by SEC columns packed with Sepharose CL-6B, Sephacryl S-400 or Superose 6PG and a ready-to-use qEV10/70 nm column. A total of 46 fractions were collected and analysed by slot-blot followed by Ponceau staining. Immunodetection was performed for albumin, EV markers CD9, CD81, and lipoprotein markers ApoE and ApoAI. The size and concentration of nanoparticles in fractions were determined by tunable resistive pulse sensing and EVs were visualised by transmission electron microscopy. We show that all four SEC techniques enabled separation of CSF into nanoparticle- and free protein-enriched fractions. Sepharose CL-6B resulted in a significantly higher number of separated EVs while lipoproteins were eluted together with free proteins. Our data indicate that Sepharose CL-6B is suitable for isolation of EVs from CSF and their separation from lipoproteins. Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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0 pages, 4658 KiB  
Article
Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma
by Kai Chen, Yingnan Si, Jia-Shiung Guan, Zhuoxin Zhou, Seulhee Kim, Taehyun Kim, Liang Shan, Christopher D. Willey, Lufang Zhou and Xiaoguang Liu
Biomedicines 2022, 10(1), 130; https://doi.org/10.3390/biomedicines10010130 - 7 Jan 2022
Cited by 9 | Viewed by 2945 | Correction
Abstract
Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound verrucarin A (Ver-A), delivered with monoclonal antibody-directed [...] Read more.
Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound verrucarin A (Ver-A), delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). First, the high surface expression of epidermal growth factor receptor (EGFR) in glioblastoma patient tissue and cell lines was confirmed using immunohistochemistry staining, flow cytometry, and Western blotting. mAb-EV-Ver-A was constructed by packing Ver-A and tagging anti-EGFR mAb to EV generated from HEK293F culture. Confocal microscopy and the In Vivo Imaging System demonstrated that mAb-EV could penetrate the blood–brain barrier, target intracranial glioblastoma xenografts, and deliver drug intracellularly. The in vitro cytotoxicity study showed IC50 values of 2–12 nM of Ver-A. The hematoxylin and eosin staining of major organs in the tolerated dose study indicated minimal systemic toxicity of mAb-EV-Ver-A. Finally, the in vivo anti-tumor efficacy study in intracranial xenograft models demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth, but the combination with VEGF mAb did not improve the therapeutic efficacy. This study suggested that mAb-EV is an effective drug delivery vehicle and natural Ver-A has great potential to treat glioblastoma. Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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12 pages, 2981 KiB  
Communication
The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p
by Delphine Garnier, Edward Ratcliffe, Joséphine Briand, Pierre-François Cartron, Lisa Oliver and François M. Vallette
Biomedicines 2022, 10(1), 112; https://doi.org/10.3390/biomedicines10010112 - 6 Jan 2022
Cited by 14 | Viewed by 2194
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, and despite initial response to chemo- and radio-therapy, the persistence of glioblastoma stem cells (GSCs) unfortunately always results in tumor recurrence. It is now largely admitted that tumor cells recruit normal cells, including mesenchymal stem [...] Read more.
Glioblastoma (GBM) is the most aggressive brain tumor, and despite initial response to chemo- and radio-therapy, the persistence of glioblastoma stem cells (GSCs) unfortunately always results in tumor recurrence. It is now largely admitted that tumor cells recruit normal cells, including mesenchymal stem cells (MSCs), and components of their environment, to participate in tumor progression, building up what is called the tumor microenvironment (TME). While growth factors and cytokines constitute essential messengers to pass on signals between tumor and TME, recent uncovering of extracellular vesicles (EVs), composed of microvesicles (MVs) and exosomes, opened new perspectives to define the modalities of this communication. In the GBM context particularly, we investigated what could be the nature of the EV exchange between GSCs and MSCs. We show that GSCs MVs can activate MSCs into cancer-associated fibroblasts (CAFs)-like cells, that subsequently increase their secretion of exosomes. Moreover, a significant decrease in anti-tumoral miR-100-5p, miR-9-5p and let-7d-5p was observed in these exosomes. This clearly suggests a miRNA-mediated GBM tumor promotion by MSCs exosomes, after their activation by GBM MVs. Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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Review

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15 pages, 599 KiB  
Review
Dynamic Intercell Communication between Glioblastoma and Microenvironment through Extracellular Vesicles
by Gloria Krapež, Katarina Kouter, Ivana Jovčevska and Alja Videtič Paska
Biomedicines 2022, 10(1), 151; https://doi.org/10.3390/biomedicines10010151 - 11 Jan 2022
Cited by 4 | Viewed by 2130
Abstract
Glioblastoma is simultaneously the most common and most aggressive primary brain tumor in the central nervous system, with poor patient survival and scarce treatment options. Most primary glioblastomas reoccur and evolve radio- and chemoresistant properties which make them resistant to further treatments. Based [...] Read more.
Glioblastoma is simultaneously the most common and most aggressive primary brain tumor in the central nervous system, with poor patient survival and scarce treatment options. Most primary glioblastomas reoccur and evolve radio- and chemoresistant properties which make them resistant to further treatments. Based on gene mutations and expression profiles, glioblastoma is relatively well classified; however, research shows that there is more to glioblastoma biology than that defined solely by its genetic component. Specifically, the overall malignancy of the tumor is also influenced by the dynamic communication to its immediate and distant environment, as important messengers to neighboring cells in the tumor microenvironment extracellular vesicles (EVs) have been identified. EVs and their cargo can modulate the immune microenvironment and other physiological processes, and can interact with the host immune system. They are involved in tumor cell survival and metabolism, tumor initiation, progression, and therapy resistance. However, on the other hand EVs are thought to become an effective treatment alternative, since they can cross the blood–brain barrier, are able of specific cell-targeting and can be loaded with various therapeutic molecules. Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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Other

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2 pages, 1669 KiB  
Correction
Correction: Chen et al. Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma. Biomedicines 2022, 10, 130
by Kai Chen, Yingnan Si, Jia-Shiung Guan, Zhuoxin Zhou, Seulhee Kim, Taehyun Kim, Liang Shan, Christopher D. Willey, Lufang Zhou and Xiaoguang Liu
Biomedicines 2024, 12(1), 86; https://doi.org/10.3390/biomedicines12010086 - 29 Dec 2023
Cited by 1 | Viewed by 629
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Small Extracellular Vesicles: A Novel Avenue for Brain Tumor Management)
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