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Extracellular Vesicles and Tumour Microenvironment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 47383

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Special Issue Editor

Dr. Francesca Margheri

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Guest Editor

Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Firenze, Italy
Interests: fibrinolytic system (uPA/uPAR system); tumour invasion and metastasis; angiogenesis; tumour extracellular vesicles; tumour microenvironment; melanoma cells; endothelial cells; cancer immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumor-derived exosomes are emerging mediators of tumorigenesis. Exosomes are small membrane extracellular vesicles (EVs) (40–150 nm) derived from the luminal membranes of multivesicular bodies and are released via fusion with the cell membrane. Exosomes contain bioactive molecules, such as nucleic acids (DNA, mRNA, miRNA, and other noncoding RNAs), proteins (receptors, transcription factors, enzymes, extracellular matrix proteins), and lipids that can redirect the function of a recipient cell. During primary tumor formation, tumor cells require active communication with neighboring cells and their local microenvironment. In recent years, the critical role of EVs in cell–cell communications between tumor cells and surrounding cells in the primary tumor microenvironment has been highlighted. Here, we focus on the role of EVs, and in particular of exosomes, as critical mediators of intracellular communication between tumor cells and stromal cells in local and distant microenvironments.

In particular, the aim of this issue is to elucidate the mode of action of exosomes and their constituents in the context of pre-metastatic niche formation and subsequent metastasis. In fact, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.

Dr. Francesca Margheri
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Tumor microenvironment
Extracellular vesicles
Exosomes
Metastasis
Interaction between tumor cells and stromal cells
Tumor progression

Published Papers (13 papers)

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Research

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15 pages, 4409 KiB

Open AccessArticle

A Possible Role of FZD10 Delivering Exosomes Derived from Colon Cancers Cell Lines in Inducing Activation of Epithelial–Mesenchymal Transition in Normal Colon Epithelial Cell Line

by Maria Principia Scavo, Federica Rizzi, Nicoletta Depalo, Elisabetta Fanizza, Chiara Ingrosso, Maria Lucia Curri and Gianluigi Giannelli

Int. J. Mol. Sci. 2020, 21(18), 6705; https://doi.org/10.3390/ijms21186705 - 13 Sep 2020

Cited by 16 | Viewed by 2605

Abstract

Exosomes belong to the family of extracellular vesicles released by every type of cell both in normal and pathological conditions. Growing interest in studies indicates that extracellular vesicles, in particular, the fraction named exosomes containing lipids, proteins and nucleic acid, represent an efficient way to transfer functional cargoes between cells, thus combining all the other cell–cell interaction mechanisms known so far. Only a few decades ago, the involvement of exosomes in the carcinogenesis in different tissues was discovered, and very recently it was also observed how they carry and modulate the presence of Wnt pathway proteins, involved in the carcinogenesis of gastrointestinal tissues, such as Frizzled 10 protein (FZD10), a membrane receptor for Wnt. Here, we report the in vitro study on the capability of tumor-derived exosomes to induce neoplastic features in normal cells. Exosomes derived from two different colon cancer cell lines, namely the non-metastatic CaCo-2 and the metastatic SW620, were found to deliver, in both cases, FZD10, thus demonstrating the ability to reprogram normal colonic epithelial cell line (HCEC-1CT). Indeed, the acquisition of specific mesenchymal characteristics, such as migration capability and expression of FZD10 and markers of mesenchymal cells, was observed. The exosomes derived from the metastatic cell line, characterized by a level of FZD10 higher than the exosomes extracted from the non-metastatic cells, were also more efficient in stimulating EMT activation. The overall results suggest that FZD10, delivered by circulating tumor-derived exosomes, can play a relevant role in promoting the CRC carcinogenesis and propagation. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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29 pages, 2396 KiB

Open AccessArticle

Proteomic Approach for Searching for Universal, Tissue-Specific, and Line-Specific Markers of Extracellular Vesicles in Lung and Colorectal Adenocarcinoma Cell Lines

by Svetlana Novikova, Natalia Shushkova, Tatiana Farafonova, Olga Tikhonova, Roman Kamyshinsky and Victor Zgoda

Int. J. Mol. Sci. 2020, 21(18), 6601; https://doi.org/10.3390/ijms21186601 - 09 Sep 2020

Cited by 10 | Viewed by 2961

Abstract

Tumor-derived extracellular vesicles (EVs), including exosomes, contain proteins that mirror the molecular landscape of producer cells. Being potentially detectible in biological fluids, EVs are of great interest for the screening of cancer biomarkers. To reveal universal, tissue-specific, and line-specific markers, we performed label-free mass spectrometric profiling of EVs originating from the human colon cancer cell lines Caco-2, HT29, and HCT-116, as well as from the lung cancer cell lines NCI-H23 and A549. A total of 651 proteins was identified in the EV samples using at least two peptides. These proteins were highly enriched in exosome markers. We found 11 universal, eight tissue-specific, and 29 line-specific markers, the levels of which were increased in EVs compared to the whole lysates. The EV proteins were involved in the EGFR, Rap1, integrin, and microRNA signaling associated with metastasis and cancer progression. An EV protein-based assay could be developed as a liquid biopsy tool. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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15 pages, 3515 KiB

Open AccessArticle

Adipose-Derived Mesenchymal Stem Cells do not Affect the Invasion and Migration Potential of Oral Squamous Carcinoma Cells

by Snehadri Sinha, Matilda Narjus-Sterba, Katja Tuomainen, Sippy Kaur, Riitta Seppänen-Kaijansinkko, Tuula Salo, Bettina Mannerström and Ahmed Al-Samadi

Int. J. Mol. Sci. 2020, 21(18), 6455; https://doi.org/10.3390/ijms21186455 - 04 Sep 2020

Cited by 12 | Viewed by 2960

Abstract

Mesenchymal stem cells (MSCs) are commonly isolated from bone marrow and adipose tissue. Depending on the tissue of origin, MSCs have different characteristics and physiological effects. In various cancer studies, MSCs have been found to have either tumor-promoting or tumor-inhibiting action. This study investigated the effect of adipose tissue-MSCs (AT-MSCs) and bone marrow-MSCs (BM-MSCs) on global long interspersed nuclear element-1 (LINE-1) methylation, the expression level of microenvironment remodeling genes and cell proliferation, migration and invasion of oral tongue squamous cell carcinoma (OTSCC). Additionally, we studied the effect of human tongue squamous carcinoma (HSC-3)-conditioned media on LINE-1 methylation and the expression of microenvironment remodeling genes in AT-MSCs and BM-MSCs. Conditioned media from HSC-3 or MSCs did not affect LINE-1 methylation level in either cancer cells or MSCs, respectively. In HSC-3 cells, no effect of MSCs-conditioned media was detected on the expression of ICAM1, ITGA3 or MMP1. On the other hand, HSC-3-conditioned media upregulated ICAM1 and MMP1 expression in both types of MSCs. Co-cultures of AT-MSCs with HSC-3 did not induce proliferation, migration or invasion of the cancer cells. In conclusion, AT-MSCs, unlike BM-MSCs, seem not to participate in oral cancer progression. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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21 pages, 4049 KiB

Open AccessArticle

Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

by Laura Patras, Marcel H. A. M. Fens, Pieter Vader, Arjan Barendrecht, Alina Sesarman, Manuela Banciu and Raymond Schiffelers

Int. J. Mol. Sci. 2020, 21(17), 5951; https://doi.org/10.3390/ijms21175951 - 19 Aug 2020

Cited by 3 | Viewed by 2823

Abstract

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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20 pages, 4308 KiB

Open AccessArticle

Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming

by Alekhya Mazumdar, Joaquin Urdinez, Aleksandar Boro, Jessica Migliavacca, Matthias J.E. Arlt, Roman Muff, Bruno Fuchs, Jess Gerrit Snedeker and Ana Gvozdenovic

Int. J. Mol. Sci. 2020, 21(15), 5451; https://doi.org/10.3390/ijms21155451 - 30 Jul 2020

Cited by 33 | Viewed by 4255

Abstract

Tumor-secreted extracellular vesicles (EVs) have been identified as mediators of cancer–host intercellular communication and shown to support pre-metastatic niche formation by modulating stromal cells at future metastatic sites. While osteosarcoma, the most common primary malignant bone tumor in children and adolescents, has a high propensity for pulmonary metastases, the interaction of osteosarcoma cells with resident lung cells remains poorly understood. Here, we deliver foundational in vitro evidence that osteosarcoma cell-derived EVs drive myofibroblast/cancer-associated fibroblast differentiation. Human lung fibroblasts displayed increased invasive competence, in addition to increased α-smooth muscle actin expression and fibronectin production upon EV treatment. Furthermore, we demonstrate, through the use of transforming growth factor beta receptor 1 (TGFBR1) inhibitors and CRISPR-Cas9-mediated knockouts, that TGFβ1 present in osteosarcoma cell-derived EVs is responsible for lung fibroblast differentiation. Overall, our study highlights osteosarcoma-derived EVs as novel regulators of lung fibroblast activation and provides mechanistic insight into how osteosarcoma cells can modulate distant cells to potentially support metastatic progression. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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13 pages, 4926 KiB

Open AccessArticle

Arginase-1+ Exosomes from Reprogrammed Macrophages Promote Glioblastoma Progression

by Juliana H. Azambuja, Nils Ludwig, Saigopalakrishna S. Yerneni, Elizandra Braganhol and Theresa L. Whiteside

Int. J. Mol. Sci. 2020, 21(11), 3990; https://doi.org/10.3390/ijms21113990 - 02 Jun 2020

Cited by 60 | Viewed by 4714

Abstract

Interactions between tumor cells and tumor-associated macrophages (TAMs) are critical for glioblastoma progression. The TAMs represent up to 30% of the glioblastoma mass. The role of TAMs in tumor progression and in the mechanisms underlying tumor growth remain unclear. Using an in vitro model resembling the crosstalk between macrophages and glioblastoma cells, we show that glioblastoma-derived exosomes (GBex) reprogram M1 (mediate pro-inflammatory function) and M2 (mediate anti-inflammatory function) macrophages, converting M1 into TAMs and augmenting pro-tumor functions of M2 macrophages. In turn, these GBex-reprogrammed TAMs, produce exosomes decorated by immunosuppressive and tumor-growth promoting proteins. TAM-derived exosomes disseminate these proteins in the tumor microenvironment (TME) promoting tumor cell migration and proliferation. Mechanisms underlying the promotion of glioblastoma growth involved Arginase-1+ exosomes produced by the reprogrammed TAMs. A selective Arginase-1 inhibitor, nor-NOHA reversed growth-promoting effects of Arginase-1 carried by TAM-derived exosomes. The data suggest that GBex-reprogrammed Arginase-1+ TAMs emerge as a major source of exosomes promoting tumor growth and as a potential therapeutic target in glioblastoma. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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17 pages, 2182 KiB

Open AccessArticle

Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

by Golnaz Morad, Cassandra C. Daisy, Hasan H. Otu, Towia A. Libermann, Simon T. Dillon and Marsha A. Moses

Int. J. Mol. Sci. 2020, 21(11), 3851; https://doi.org/10.3390/ijms21113851 - 28 May 2020

Cited by 20 | Viewed by 3271

Abstract

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood–brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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Review

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38 pages, 1197 KiB

Open AccessReview

The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

by Issraa Shoucair, Fernanda Weber Mello, James Jabalee, Saeideh Maleki and Cathie Garnis

Int. J. Mol. Sci. 2020, 21(18), 6837; https://doi.org/10.3390/ijms21186837 - 17 Sep 2020

Cited by 45 | Viewed by 5205

Abstract

Extracellular vesicles (EVs) play a key role in the communication between cancer cells and stromal components of the tumor microenvironment (TME). In this context, cancer cell-derived EVs can regulate the activation of a CAF phenotype in TME cells, which can be mediated by several EV cargos (e.g., miRNA, proteins, mRNA and lncRNAs). On the other hand, CAF-derived EVs can mediate several processes during tumorigenesis, including tumor growth, invasion, metastasis, and therapy resistance. This review aimed to discuss the molecular aspects of EV-based cross-talk between CAFs and cancer cells during tumorigenesis, in addition to assessing the roles of EV cargo in therapy resistance and pre-metastatic niche formation. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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21 pages, 1787 KiB

Open AccessReview

Extracellular Vesicles in the Tumour Microenvironment: Eclectic Supervisors

by Claudia Cavallari, Giovanni Camussi and Maria Felice Brizzi

Int. J. Mol. Sci. 2020, 21(18), 6768; https://doi.org/10.3390/ijms21186768 - 15 Sep 2020

Cited by 16 | Viewed by 3350

Abstract

The tumour microenvironment (TME) plays a crucial role in the regulation of cell survival and growth by providing inhibitory or stimulatory signals. Extracellular vesicles (EV) represent one of the most relevant cell-to-cell communication mechanism among cells within the TME. Moreover, EV contribute to the crosstalk among cancerous, immune, endothelial, and stromal cells to establish TME diversity. EV contain proteins, mRNAs and miRNAs, which can be locally delivered in the TME and/or transferred to remote sites to dictate tumour behaviour. EV in the TME impact on cancer cell proliferation, invasion, metastasis, immune-escape, pre-metastatic niche formation and the stimulation of angiogenesis. Moreover, EV can boost or inhibit tumours depending on the TME conditions and their cell of origin. Therefore, to move towards the identification of new targets and the development of a novel generation of EV-based targeting approaches to gain insight into EV mechanism of action in the TME would be of particular relevance. The aim here is to provide an overview of the current knowledge of EV released from different TME cellular components and their role in driving TME diversity. Moreover, recent proposed engineering approaches to targeting cells in the TME via EV are discussed. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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17 pages, 1517 KiB

Open AccessReview

Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets

by Takaaki Tamura, Yusuke Yoshioka, Shinichi Sakamoto, Tomohiko Ichikawa and Takahiro Ochiya

Int. J. Mol. Sci. 2020, 21(18), 6680; https://doi.org/10.3390/ijms21186680 - 12 Sep 2020

Cited by 17 | Viewed by 3503

Abstract

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis. Bone is a preferred site of metastasis, and bone metastasis is generally incurable and dramatically affects patient quality of life. Bone metastasis can cause devastating complications, including hypercalcemia, pathological fractures, spinal compression, and bone pain, which result in a poor prognosis. Although the mechanisms underlying bone metastasis have yet to be fully elucidated, increasing evidence suggests that EVs in the bone microenvironment significantly contribute to cancer progression and cancer bone tropism. Emerging evidence on EV functions in bone metastasis will facilitate the discovery of novel treatments. In this review, we will discuss the remarkable effects of EVs, especially on the tumor microenvironment in bone. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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32 pages, 2633 KiB

Open AccessReview

EVs and Bioengineering: From Cellular Products to Engineered Nanomachines

by Simona Villata, Marta Canta and Valentina Cauda

Int. J. Mol. Sci. 2020, 21(17), 6048; https://doi.org/10.3390/ijms21176048 - 22 Aug 2020

Cited by 52 | Viewed by 4408

Abstract

Extracellular vesicles (EVs) are natural carriers produced by many different cell types that have a plethora of functions and roles that are still under discovery. This review aims to be a compendium on the current advancement in terms of EV modifications and re-engineering, as well as their potential use in nanomedicine. In particular, the latest advancements on artificial EVs are discussed, with these being the frontier of nanomedicine-based therapeutics. The first part of this review gives an overview of the EVs naturally produced by cells and their extraction methods, focusing on the possibility to use them to carry desired cargo. The main issues for the production of the EV-based carriers are addressed, and several examples of the techniques used to upload the cargo are provided. The second part focuses on the engineered EVs, obtained through surface modification, both using direct and indirect methods, i.e., engineering of the parental cells. Several examples of the current literature are proposed to show the broad variety of engineered EVs produced thus far. In particular, we also report the possibility to engineer the parental cells to produce cargo-loaded EVs or EVs displaying specific surface markers. The third and last part focuses on the most recent advancements based on synthetic and chimeric EVs and the methods for their production. Both top-down or bottom-up techniques are analyzed, with many examples of applications. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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20 pages, 856 KiB

Open AccessReview

Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers

by Lyna Kara-Terki, Lucas Treps, Christophe Blanquart and Delphine Fradin

Int. J. Mol. Sci. 2020, 21(17), 6024; https://doi.org/10.3390/ijms21176024 - 21 Aug 2020

Cited by 12 | Viewed by 3403

Abstract

Extracellular vesicles (EVs), such as exosomes, are critical mediators of intercellular communication between tumor cells and other cells located in the microenvironment but also in more distant sites. Exosomes are small EVs that can carry a variety of molecules, such as lipids, proteins, and non-coding RNA, especially microRNAs (miRNAs). In thoracic cancers, including lung cancers and malignant pleural mesothelioma, EVs contribute to the immune-suppressive tumor microenvironment and to tumor growth and metastasis. In this review, we discuss the recent understanding of how exosomes behave in thoracic cancers and how and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy, with a special focus on exosomal miRNAs. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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17 pages, 1444 KiB

Open AccessReview

Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

by Song Yi Ko and Honami Naora

Int. J. Mol. Sci. 2020, 21(15), 5418; https://doi.org/10.3390/ijms21155418 - 30 Jul 2020

Cited by 29 | Viewed by 3175

Abstract

The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)

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