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Extracellular Vesicles and Metastatic Niche

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

Deadline for manuscript submissions: closed (10 June 2019) | Viewed by 63704

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Prof. Vincenza Dolo

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Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
Interests: extracellular vesicles; tumor progression; electron microscopy
Special Issues, Collections and Topics in MDPI journals

Dr. Ilaria Giusti

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Guest Editor

Departement of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
Interests: extracellular vesicles; tumor microenvironment; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Extracellular vesicles (EVs) are membrane-enclosed particles released by both normal and tumor cells that operate as heterogeneous multisignal messengers involved in cell-to cell communication.

In cancer, EVs mediate the tumor-stroma interaction affecting, among other things, cell proliferation, angiogenesis, immune surveillance and drug resistance, thus supporting cancer growth. The tumor promoting activities of EVs are not restricted to local tumor microenvironment but also include dissemination, since EVs can enter the blood circulation, reach distant organs and, there, educate resident cells to generate favorable environmental conditions; this process is known as pre-metastatich niche formation.

This Special Issue, “Extracellular Vesicles and Metastatic Niche”, of the International Journal of Molecular Sciences will comprise a selection of research papers and reviews covering various aspects of biochemistry, molecular and cellular biology on the role of EVs in the metastatich niche. Contributions on cell-signaling pathways involved, functional studies, molecular characterization as well as their impact on possible clinical implications, will be welcome. Studies on the set up of specific in vitro and in vivo models will also be considered.

Prof. Vincenza Dolo
Dr. Ilaria Giusti
Guest Editors

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Keywords

Extracellular vesicles
Metastatic niche
Cancer
EMT
Exosomes
Metastasis
Microvesicles
Tumor dormancy
Tumor microenvironment

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Extracellular Vesicles and Metastatic Niche 2.0 in International Journal of Molecular Sciences (4 articles)

Published Papers (11 papers)

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Research

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17 pages, 2118 KiB

Open AccessArticle

Extracellular Vesicles Released by Colorectal Cancer Cell Lines Modulate Innate Immune Response in Zebrafish Model: The Possible Role of Human Endogenous Retroviruses

by Luca Ferrari, Marco Cafora, Federica Rota, Mirjam Hoxha, Simona Iodice, Letizia Tarantini, Maria Dolci, Serena Delbue, Anna Pistocchi and Valentina Bollati

Int. J. Mol. Sci. 2019, 20(15), 3669; https://doi.org/10.3390/ijms20153669 - 26 Jul 2019

Cited by 13 | Viewed by 3764

Abstract

Extracellular vesicles (EVs) are important components of the metastatic niche and are crucial in infiltration, metastasis, and immune tolerance processes during tumorigenesis. We hypothesized that human endogenous retroviruses (HERV) positive EVs derived from tumor cellsmay have a role in modulating the innate immune response. The study was conducted in two different colorectal cancer cell lines, representing different stages of cancer development: Caco-2, derived from a non-metastatic colorectal adenocarcinoma, and SK-CO-1, derived from metastatic colorectal adenocarcinoma (ascites). Both cell lines were treated with decitabine to induce global hypomethylation and to reactivate HERV expression. EVs were quantified by nanoparticle tracking analysis, and HERV-positive EV concentrations were measured by flow cytometry. The effect of EVs isolated from both untreated and decitabine-treated cells on the innate immune response was evaluated by injecting them in zebrafish embryos and then assessing Interleukin 1β (IL1-β), Interleukin 10 (IL-10), and the myeloperoxidase (mpx) expression levels by real-time qPCR. Interestingly, HERV-K positive EVs concentrations were significantly associated with a reduced expression of IL1-β and mpx, supporting our hypothesis that HERV-positive EVs may act as immunomodulators in tumor progression. The obtained results open new perspectives about the modulation of the immune response in cancer therapy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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12 pages, 1920 KiB

Open AccessArticle

Unravelling the Role of Trophoblastic-Derived Extracellular Vesicles in Regulatory T Cell Differentiation

by Árpád Ferenc Kovács, Nóra Fekete, Lilla Turiák, András Ács, László Kőhidai, Edit I. Buzás and Éva Pállinger

Int. J. Mol. Sci. 2019, 20(14), 3457; https://doi.org/10.3390/ijms20143457 - 14 Jul 2019

Cited by 37 | Viewed by 5805

Abstract

Regulatory T cells (T_reg) are mandatory elements in the maintenance of human pregnancy, but their de novo differentiation has not been completely exposed. HSPE1 chaperone expressing trophoblast cells may have a role in it. Trophoblast-derived extracellular vesicles (EVs), either at the feto–maternal interface or in circulation, target CD4⁺ T cells. We hypothesized that HSPE1-associated trophoblastic cell line (BeWo)-derived EVs are active mediators of T_reg cell differentiation. We proved at first that recombinant HSPE1 promote human T_reg cell differentiation in vitro. Developing a CRISPR-Cas9 based HSPE1 knockout BeWo cell line we could also demonstrate, that EV-associated HSPE1 induces T_reg development. Next-generation sequencing of miRNA cargo of BeWo-EVs characterized the regulatory processes of T_reg polarization. By the use of single-cell transcriptomics analysis, seven T_reg cell subtypes were distinguished and we demonstrated for the first time that the expression level of HSPE1 was T_reg subtype dependent, and CAPG expression is characteristic to memory phenotype of T cells. Our data indicate that HSPE1 and CAPG may be used as markers for identification of T_reg subtypes. Our results suggest, that trophoblastic-derived iEVs-associated HSPE1 and miRNA cargo have an important role in T_reg cell expansion in vitro and HSPE1 is a useful marker of T_reg subtype characterization. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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19 pages, 4927 KiB

Open AccessArticle

NOS2 inhibitor 1400W Induces Autophagic Flux and Influences Extracellular Vesicle Profile in Human Glioblastoma U87MG Cell Line

by Paola Palumbo, Francesca Lombardi, Francesca Rosaria Augello, Ilaria Giusti, Sabino Luzzi, Vincenza Dolo, Maria Grazia Cifone and Benedetta Cinque

Int. J. Mol. Sci. 2019, 20(12), 3010; https://doi.org/10.3390/ijms20123010 - 20 Jun 2019

Cited by 49 | Viewed by 4259

Abstract

The relevance of nitric oxide synthase 2 (NOS2) as a prognostic factor in Glioblastoma Multiforme (GBM) malignancy is emerging. We analyzed the effect of NOS2 inhibitor 1400W on the autophagic flux and extracellular vesicle (EV) secretion in U87MG glioma cells. The effects of glioma stem cells (GSC)-derived EVs on adherent U87MG were evaluated. Cell proliferation and migration were examined while using Cell Counting Kit-8 assay (CCK-8) and scratch wound healing assay. Cell cycle profile and apoptosis were analyzed by flow cytometry. Autophagy-associated acidic vesicular organelles were detected and quantified by acridine orange staining. The number and size of EVs were assessed by nanoparticle tracking analysis. EV ultrastructure was verified by transmission electron microscopy (TEM). WB was used to analyze protein expression and acid sphingomyelinase was determined through ceramide levels. 1400W induced autophagy and EV secretion in both adherent U87MG and GSCs. EVs secreted by 1400W-treated GSC, but not those from untreated cells, were able to inhibit adherent U87MG cell growth and migration while also inducing a relevant level of autophagy. The hypothesis of NOS2 expression as GBM profile marker or interesting therapeutic target is supported by our findings. Autophagy and EV release following treatment with the NOS2 inhibitor could represent useful elements to better understand the complex biomolecular frame of GBM. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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17 pages, 16737 KiB

Open AccessArticle

Gastric Cancer Extracellular Vesicles Tune the Migration and Invasion of Epithelial and Mesenchymal Cells in a Histotype-Dependent Manner

by Sara Rocha, Sara Pinto Teles, Mafalda Azevedo, Patrícia Oliveira, Joana Carvalho and Carla Oliveira

Int. J. Mol. Sci. 2019, 20(11), 2608; https://doi.org/10.3390/ijms20112608 - 28 May 2019

Cited by 8 | Viewed by 4373

Abstract

Extracellular vesicles (EVs) secreted by tumor cells modulate recipient cells’ behavior, but their effects in normal cells from the tumor microenvironment remain poorly known. In this study, we dissected the functional impact of gastric cancer cell-derived EVs (GC-EVs), representative of distinct GC histotypes, on the behavior of normal isogenic epithelial and mesenchymal cells. GC-EVs were isolated by differential centrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and imaging flow-cytometry. Epithelial and mesenchymal cells were challenged with GC-EVs and submitted to proliferation, migration, and invasion assays. Expression of epithelial and mesenchymal markers was followed by immunofluorescence and flow-cytometry. Our results indicated that GC-EVs secreted by diffuse-type cancer cells decrease the migration of recipient cells. This effect was more prominent and persistent for mesenchymal recipient cells, which also increased Fibronectin expression in response to EVs. GC-EVs secreted by cancer cells derived from tumors with an intestinal component increased invasion of recipient epithelial cells, without changes in EMT markers. In summary, this study demonstrated that GC-EVs modulate the migration and invasion of epithelial and mesenchymal cells from the tumor microenvironment, in a histotype-dependent manner, highlighting new features of intestinal and diffuse-type GC cells, which may help explaining differential metastasis patterns and aggressiveness of GC histotypes. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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13 pages, 3731 KiB

Open AccessArticle

Analysis of Extracellular Vesicles in Gastric Juice from Gastric Cancer Patients

by Shuji Kagota, Kohei Taniguchi, Sang-Woong Lee, Yuko Ito, Yuki Kuranaga, Yasuyuki Hashiguchi, Yosuke Inomata, Yoshiro Imai, Ryo Tanaka, Keitaro Tashiro, Masaru Kawai, Yukihiro Akao and Kazuhisa Uchiyama

Int. J. Mol. Sci. 2019, 20(4), 953; https://doi.org/10.3390/ijms20040953 - 22 Feb 2019

Cited by 29 | Viewed by 5258

Abstract

Extracellular vesicles (EVs) are secretory membrane vesicles containing lipids, proteins, and nucleic acids; they function in intercellular transport by delivering their components to recipient cells. EVs are observed in various body fluids, i.e., blood, saliva, urine, amniotic fluid, and ascites. EVs secreted from cancer cells play important roles in the formation of their environment, including fibrosis, angiogenesis, evasion of immune surveillance, and even metastasis. However, EVs in gastric juice (GJ-EVs) have been largely unexplored. In this study, we sought to clarify the existence of GJ-EVs derived from gastric cancer patients. GJ-EVs were isolated by the ultracentrifuge method combined with our own preprocessing from gastric cancer (GC) patients. We verified GJ-EVs by morphological experiments, i.e., nanoparticle tracking system analysis and electron microscopy. In addition, protein and microRNA markers of EVs were examined by Western blotting analysis, Bioanalyzer, or quantitative reverse transcription polymerase chain reaction. GJ-EVs were found to promote the proliferation of normal fibroblast cells. Our findings suggest that isolates from the GJ of GC patients contain EVs and imply that GJ-EVs partially affect their microenvironments and that analysis using GJ-EVs from GC patients will help to clarify the pathophysiology of GC. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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23 pages, 3988 KiB

Open AccessArticle

Peptidylarginine Deiminases Post-Translationally Deiminate Prohibitin and Modulate Extracellular Vesicle Release and MicroRNAs in Glioblastoma Multiforme

by Uchini S. Kosgodage, Pinar Uysal-Onganer, Amy MacLatchy, Igor Kraev, Nicholas P. Chatterton, Anthony P. Nicholas, Jameel M. Inal and Sigrun Lange

Int. J. Mol. Sci. 2019, 20(1), 103; https://doi.org/10.3390/ijms20010103 - 28 Dec 2018

Cited by 52 | Viewed by 6803

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of adult primary malignant brain tumour with poor prognosis. Extracellular vesicles (EVs) are a key-mediator through which GBM cells promote a pro-oncogenic microenvironment. Peptidylarginine deiminases (PADs), which catalyze the post-translational protein deimination of target proteins, are implicated in cancer, including via EV modulation. Pan-PAD inhibitor Cl-amidine affected EV release from GBM cells, and EV related microRNA cargo, with reduced pro-oncogenic microRNA21 and increased anti-oncogenic microRNA126, also in combinatory treatment with the chemotherapeutic agent temozolomide (TMZ). The GBM cell lines under study, LN18 and LN229, differed in PAD2, PAD3 and PAD4 isozyme expression. Various cytoskeletal, nuclear and mitochondrial proteins were identified to be deiminated in GBM, including prohibitin (PHB), a key protein in mitochondrial integrity and also involved in chemo-resistance. Post-translational deimination of PHB, and PHB protein levels, were reduced after 1 h treatment with pan-PAD inhibitor Cl-amidine in GBM cells. Histone H3 deimination was also reduced following Cl-amidine treatment. Multifaceted roles for PADs on EV-mediated pathways, as well as deimination of mitochondrial, nuclear and invadopodia related proteins, highlight PADs as novel targets for modulating GBM tumour communication. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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Review

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27 pages, 1078 KiB

Open AccessReview

Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers

by Suet Yen Chong, Choon Keong Lee, Chenyuan Huang, Yi Hsuan Ou, Christopher J. Charles, Arthur Mark Richards, Yub Raj Neupane, Maria Vazquez Pavon, Olga Zharkova, Giorgia Pastorin and Jiong-Wei Wang

Int. J. Mol. Sci. 2019, 20(13), 3272; https://doi.org/10.3390/ijms20133272 - 3 Jul 2019

Cited by 92 | Viewed by 8556

Abstract

Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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15 pages, 2487 KiB

Open AccessReview

Extracellular Vesicles Enhance Multiple Myeloma Metastatic Dissemination

by Michela Colombo, Domenica Giannandrea, Elena Lesma, Andrea Basile and Raffaella Chiaramonte

Int. J. Mol. Sci. 2019, 20(13), 3236; https://doi.org/10.3390/ijms20133236 - 1 Jul 2019

Cited by 39 | Viewed by 5569

Abstract

Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures shed by all kinds of cell types, which are released into the surrounding microenvironment or spread to distant sites through the circulation. Therefore, EVs are key mediators of the communication between tumor cells and the surrounding microenvironment or the distant premetastatic niche due to their ability to transport lipids, transcription factors, mRNAs, non-coding regulatory RNAs, and proteins. Multiple myeloma (MM) is a hematological neoplasm that mostly relies on the bone marrow (BM). The BM represents a highly supportive niche for myeloma establishment and diffusion during the formation of distant bone lesions typical of this disease. This review represents a survey of the most recent evidence published on the role played by EVs in supporting MM cells during the multiple steps of metastasis, including travel and uptake at distant premetastatic niches, MM cell engraftment as micrometastasis, and expansion to macrometastasis thanks to EV-induced angiogenesis, release of angiocrine factors, activation of osteolytic activity, and mesenchymal cell support. Finally, we illustrate the first evidence concerning the dual effect of MM-EVs in promoting both anti-tumor immunity and MM immune escape, and the possible modulation operated by pharmacological treatments. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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17 pages, 738 KiB

Open AccessReview

Metastatic Niches and the Modulatory Contribution of Mesenchymal Stem Cells and Its Exosomes

by Matias Valenzuela Alvarez, Luciana M. Gutierrez, Alejandro Correa, Alberto Lazarowski and Marcela F. Bolontrade

Int. J. Mol. Sci. 2019, 20(8), 1946; https://doi.org/10.3390/ijms20081946 - 20 Apr 2019

Cited by 23 | Viewed by 5799

Abstract

Mesenchymal stem cells (MSCs) represent an interesting population due to their capacity to release a variety of cytokines, chemokines, and growth factors, and due to their motile nature and homing ability. MSCs can be isolated from different sources, like adipose tissue or bone marrow, and have the capacity to differentiate, both in vivo and in vitro, into adipocytes, chondrocytes, and osteoblasts, making them even more interesting in the regenerative medicine field. Tumor associated stroma has been recognized as a key element in tumor progression, necessary for the biological success of the tumor, and MSCs represent a functionally fundamental part of this associated stroma. Exosomes represent one of the dominant signaling pathways within the tumor microenvironment. Their biology raises high interest, with implications in different biological processes involved in cancer progression, such as the formation of the pre-metastatic niche. This is critical during the metastatic cascade, given that it is the formation of a permissive context that would allow metastatic tumor cells survival within the new environment. In this context, we explored the role of exosomes, particularly MSCs-derived exosomes as direct or indirect modulators. All this points out a possible new tool useful for designing better treatment and detection strategies for metastatic progression, including the management of chemoresistance. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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16 pages, 518 KiB

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Extracellular Vesicles and Carried miRNAs in the Progression of Renal Cell Carcinoma

by Cristina Grange, Alessia Brossa and Benedetta Bussolati

Int. J. Mol. Sci. 2019, 20(8), 1832; https://doi.org/10.3390/ijms20081832 - 13 Apr 2019

Cited by 43 | Viewed by 5080

Abstract

The formation and maintenance of renal cell carcinomas (RCC) involve many cell types, such as cancer stem and differentiated cells, endothelial cells, fibroblasts and immune cells. These all contribute to the creation of a favorable tumor microenvironment to promote tumor growth and metastasis. Extracellular vesicles (EVs) are considered to be efficient messengers that facilitate the exchange of information within the different tumor cell types. Indeed, tumor EVs display features of their originating cells and force recipient cells towards a pro-tumorigenic phenotype. This review summarizes the recent knowledge related to the biological role of EVs, shed by renal tumor cells and renal cancer stem cells in different aspects of RCC progression, such as angiogenesis, immune escape and tumor growth. Moreover, a specific role for renal cancer stem cell derived EVs is described in the formation of the pre-metastatic niche. We also highlight the tumor EV cargo, especially the oncogenic miRNAs, which are involved in these processes. Finally, the circulating miRNAs appear to be a promising source of biomarkers in RCC. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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18 pages, 285 KiB

Open AccessReview

Bladder Cancer Diagnosis and Follow-Up: The Current Status and Possible Role of Extracellular Vesicles

by Eline Oeyen, Lucien Hoekx, Stefan De Wachter, Marcella Baldewijns, Filip Ameye and Inge Mertens

Int. J. Mol. Sci. 2019, 20(4), 821; https://doi.org/10.3390/ijms20040821 - 14 Feb 2019

Cited by 89 | Viewed by 7709

Abstract

Diagnostic methods currently used for bladder cancer are cystoscopy and urine cytology. Cystoscopy is an invasive tool and has low sensitivity for carcinoma in situ. Urine cytology is non-invasive, is a low-cost method, and has a high specificity but low sensitivity for low-grade urothelial tumors. Despite the search for urinary biomarkers for the early and non-invasive detection of bladder cancer, no biomarkers are used at the present in daily clinical practice. Extracellular vesicles (EVs) have been recently studied as a promising source of biomarkers because of their role in intercellular communication and tumor progression. In this review, we give an overview of Food and Drug Administration (FDA)-approved urine tests to detect bladder cancer and why their use is not widespread in clinical practice. We also include non-FDA approved urinary biomarkers in this review. We describe the role of EVs in bladder cancer and their possible role as biomarkers for the diagnosis and follow-up of bladder cancer patients. We review recently discovered EV-derived biomarkers for the diagnosis of bladder cancer. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)

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