The key roles of cancer stem cell-derived extracellular vesicles

AbstractCancer stem cells (CSCs), the subpopulation of cancer cells, have the capability of proliferation, self-renewal, and differentiation. The presence of CSCs is a key factor leading to tumor progression and metastasis. Extracellular vesicles (EVs) are nano-sized particles released by different kinds of cells and have the capacity to deliver certain cargoes, such as nucleic acids, proteins, and lipids, which have been recognized as a vital mediator in cell-to-cell communication. Recently, more and more studies have reported that EVs shed by CSCs make a significant contribution to tumor progression. CSCs-derived EVs are involved in tumor resistance, metastasis, angiogenesis, as well as the maintenance of stemness phenotype and tumor immunosuppression microenvironment. Here, we summarized the molecular mechanism by which CSCs-derived EVs in tumor progression. We believed that the fully understanding of the roles of CSCs-derived EVs in tumor development will definitely provide new ideas for CSCs-based therapeutic strategies.

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Exploiting Manipulated Small Extracellular Vesicles to Subvert Immunosuppression at the Tumor Microenvironment through Mannose Receptor/CD206 Targeting

International Journal of Molecular Sciences ◽

10.3390/ijms21176318 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6318 ◽

Cited By ~ 1

Author(s):

Maria Luisa Fiani ◽

Valeria Barreca ◽

Massimo Sargiacomo ◽

Flavia Ferrantelli ◽

Francesco Manfredi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Solid Tumors ◽

Extracellular Vesicles ◽

Biochemical Characterization ◽

Critical Role ◽

Tumor Development ◽

Cell Communication ◽

Mannose Receptor ◽

Therapeutic Molecules ◽

Ideal Tool

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.

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The Crosstalk between Cancer Stem Cells and Microenvironment Is Critical for Solid Tumor Progression: The Significant Contribution of Extracellular Vesicles

Stem Cells International ◽

10.1155/2018/6392198 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Chiara Ciardiello ◽

Alessandra Leone ◽

Alfredo Budillon

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Progression ◽

Cell Fate ◽

Extracellular Vesicles ◽

Significant Contribution ◽

Critical Role ◽

Mediated Communication

Several evidences nowadays demonstrated the critical role of the microenvironment in regulating cancer stem cells and their involvement in tumor progression. Extracellular vesicles (EVs) are considered as one of the most effective vehicles of information among cells. Accordingly, a number of studies led to the recognition of stem cell-associated EVs as new complexes able to contribute to cell fate determination of either normal or tumor cells. In this review, we aim to highlight an existing bidirectional role of EV-mediated communication—from cancer stem cells to microenvironment and also from microenvironment to cancer stem cells—in the most widespread solid cancers as prostate, breast, lung, and colon tumors.

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A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

Cancers ◽

10.3390/cancers12020298 ◽

2020 ◽

Vol 12 (2) ◽

pp. 298 ◽

Cited By ~ 15

Author(s):

Ancuta Jurj ◽

Oana Zanoaga ◽

Cornelia Braicu ◽

Vladimir Lazar ◽

Ciprian Tomuleasa ◽

...

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Tumor Development ◽

Cell Communication ◽

Cancer Diagnostics ◽

Target Cells ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Comprehensive Picture

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics.

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The role of the metabolite cargo of extracellular vesicles in tumor progression

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-10014-2 ◽

2021 ◽

Author(s):

Mária Harmati ◽

Mátyás Bukva ◽

Tímea Böröczky ◽

Krisztina Buzás ◽

Edina Gyukity-Sebestyén

Keyword(s):

Tumor Progression ◽

Extracellular Vesicles ◽

Biomarker Discovery ◽

Tumor Development ◽

Living Cells ◽

Pathological Conditions ◽

Membrane Bound ◽

And Function

AbstractMetabolomic reprogramming in tumor and stroma cells is a hallmark of cancer but understanding its effects on the metabolite composition and function of tumor-derived extracellular vesicles (EVs) is still in its infancy. EVs are membrane-bound sacs with a complex molecular composition secreted by all living cells. They are key mediators of intercellular communication both in normal and pathological conditions and play a crucial role in tumor development. Although lipids are major components of EVs, most of the EV cargo studies have targeted proteins and nucleic acids. The potential of the EV metabolome as a source for biomarker discovery has gained recognition recently, but knowledge on the biological activity of tumor EV metabolites still remains limited. Therefore, we aimed (i) to compile the list of metabolites identified in tumor EVs isolated from either clinical specimens or in vitro samples and (ii) describe their role in tumor progression through literature search and pathway analysis.

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Glioma-derived extracellular vesicles promote tumor progression by conveying WT1

Carcinogenesis ◽

10.1093/carcin/bgaa052 ◽

2020 ◽

Vol 41 (9) ◽

pp. 1238-1245

Author(s):

Taishi Tsutsui ◽

Hironori Kawahara ◽

Ryouken Kimura ◽

Yu Dong ◽

Shabierjiang Jiapaer ◽

...

Keyword(s):

Gene Expression ◽

Tumor Progression ◽

Communication Networks ◽

Extracellular Vesicles ◽

Wilms Tumor ◽

Cell Communication ◽

Negative Regulator ◽

Primary Tumors ◽

Model Mouse ◽

The Central Nervous System

Abstract Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell–cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1–Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target.

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Separation of Extracellular Vesicles by DNA-Directed Immunocapturing Followed by Enzymatic Release

10.26434/chemrxiv.12234683 ◽

2020 ◽

Author(s):

Dario Brambilla ◽

Laura Sola ◽

Elisa Chiodi ◽

Natasa Zarovni ◽

Diogo Fortunato ◽

...

Keyword(s):

Cell Culture ◽

Extracellular Vesicles ◽

Culture Media ◽

Biological Fluids ◽

Imaging Techniques ◽

Cell Communication ◽

Disease Diagnosis ◽

Cell Culture Supernatant ◽

Transmission Electron ◽

Downstream Analysis

Extracellular vesicles (EVs) have attracted great interest among researchers due to their role in cell-cell communication, disease diagnosis, and drug delivery. In spite of their potential in the medical field, there is no consensus on the best method for separating microvesicles from cell culture supernatant and complex biological fluids. Obtaining a good recovery yield and preserving physical characteristics is critical for the diagnostic and therapeutic use of EVs. The separation is made complex by the fact that blood and cell culture media, contain a large number of nanoparticles in the same size range. Methods that exploit immunoaffinity capture provide high purity samples and overcome the issues of currently used separation methods. However, the release of captured nanovesicles requires harsh conditions that hinder their use in certain types of downstream analysis. Herein, a novel capture and release approach for small extracellular vesicles (sEVs), based on DNAdirected immobilization of antiCD63 antibody is presented. The flexible DNAlinker increases the capture efficiency and allows releasing of EVs by exploiting the endonucleasic activity of DNAse I. This separation protocol works under mild conditions, enabling the release of intact vesicles that can be successfully analyzed by imaging techniques. In this article sEVs recovered from plasma were characterized by established techniques for EVs analysis including nanoparticle tracking and transmission electron microscopy.<br>

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Multiple Roles of Exosomal Long Noncoding RNAs in Cancers

BioMed Research International ◽

10.1155/2019/1460572 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Wenyuan Zhao ◽

Yuanqi Liu ◽

Chunfang Zhang ◽

Chaojun Duan

Keyword(s):

Extracellular Vesicles ◽

Cancer Diagnosis ◽

Tumor Angiogenesis ◽

Cell Communication ◽

Noncoding Rnas ◽

Multiple Roles ◽

Long Noncoding Rnas ◽

Cancer Therapies ◽

Transcriptional Noise ◽

Intercellular Exchange

Long noncoding RNAs (lncRNAs) are not transcriptional noise, as previously understood, but are currently considered to be multifunctional. Exosomes are derived from the internal multivesicular compartment and are extracellular vesicles (EVs) with diameters of 30–100 nm. Exosomes play significant roles in the intercellular exchange of information and material. Exosomal lncRNAs may be promising biomarkers for cancer diagnosis and potential targets for cancer therapies, since they are increasingly understood to be involved in tumorigenesis, tumor angiogenesis, and chemoresistance. This review mainly focuses on the roles of emerging exosomal lncRNAs in cancer. In addition, the biogenesis of exosomes, the functions of lncRNAs, and the mechanisms of lncRNAs in exosome-mediated cell-cell communication are also summarized.

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CSF extracellular vesicles and risk of disease activity after a first demyelinating event

Multiple Sclerosis Journal ◽

10.1177/1352458520987542 ◽

2021 ◽

pp. 135245852098754

Author(s):

Gloria Dalla Costa ◽

Tommaso Croese ◽

Marco Pisa ◽

Annamaria Finardi ◽

Lorena Fabbella ◽

...

Keyword(s):

Disease Activity ◽

Extracellular Vesicles ◽

Prognostic Markers ◽

Cell Communication ◽

Extracellular Vesicle ◽

Intervention Strategies ◽

Targeted Intervention ◽

Improve Risk Stratification ◽

Risk Of Disease ◽

In Cis

Background: Extracellular vesicles (EVs), a recently described mechanism of cell communication, are released from activated microglial cells and macrophages and are a candidate biomarker in diseases characterized by chronic inflammatory process such as multiple sclerosis (MS). Methods: We explored cerebrospinal fluid extracellular vesicle (CSF EV) of myeloid origin (MEVs), cytokine and chemokine levels in patients with clinically isolated syndrome (CIS). Results: We found that CSF MEVs were significantly higher in CIS patients than in controls and were inversely correlated to CSF CCL2 levels. MEVs level were significantly associated with an shorter time to evidence of disease activity (hazard ratio: 1.01, 95% confidence interval: 1.00–1.02, p < 0.01) independently from other known prognostic markers. Conclusion: After a first demyelinating event, CSF EVs may improve risk stratification of these patients and allow more targeted intervention strategies.

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Glycosylation of Cancer Extracellular Vesicles: Capture Strategies, Functional Roles and Potential Clinical Applications

Cells ◽

10.3390/cells10010109 ◽

2021 ◽

Vol 10 (1) ◽

pp. 109

Author(s):

Álvaro M. Martins ◽

Cátia C. Ramos ◽

Daniela Freitas ◽

Celso A. Reis

Keyword(s):

Extracellular Vesicles ◽

Biomarker Discovery ◽

De Novo ◽

Recipient Cell ◽

Cell Communication ◽

Cancer Biomarkers ◽

Functional Roles ◽

Molecular Information ◽

Glycosylation Pathway ◽

Organ Tropism

Glycans are major constituents of extracellular vesicles (EVs). Alterations in the glycosylation pathway are a common feature of cancer cells, which gives rise to de novo or increased synthesis of particular glycans. Therefore, glycans and glycoproteins have been widely used in the clinic as both stratification and prognosis cancer biomarkers. Interestingly, several of the known tumor-associated glycans have already been identified in cancer EVs, highlighting EV glycosylation as a potential source of circulating cancer biomarkers. These particles are crucial vehicles of cell–cell communication, being able to transfer molecular information and to modulate the recipient cell behavior. The presence of particular glycoconjugates has been described to be important for EV protein sorting, uptake and organ-tropism. Furthermore, specific EV glycans or glycoproteins have been described to be able to distinguish tumor EVs from benign EVs. In this review, the application of EV glycosylation in the development of novel EV detection and capture methodologies is discussed. In addition, we highlight the potential of EV glycosylation in the clinical setting for both cancer biomarker discovery and EV therapeutic delivery strategies.

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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽

10.3390/cancers13010068 ◽

2020 ◽

Vol 13 (1) ◽

pp. 68

Author(s):

Fulvio Massaro ◽

Florent Corrillon ◽

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Laurence Lagneaux ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Progression ◽

Cancer Progression ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Communication ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Wide Range ◽

Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

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