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Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy...
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Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Intracellular and Plasma Membranes".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 47650

Special Issue Editors

Dr. Fabrizio Fontana

E-Mail Website
Guest Editor
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
Interests: prostate cancer; melanoma; ovarian cancer; cancer biology; mechanisms of cancer cell death; cancer metastasis; cancer metabolism; cancer drug resistance; cancer stem cells; tumor microenvironment; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Felice Brizzi

E-Mail Website
Guest Editor
Department of Medical Sciences, University of Turin, Turin, Italy
Interests: EVs in tumors and inflammatory disorders
Dr. Priya Samuel

E-Mail Website
Guest Editor
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK
Interests: EVs in cancer drug resistance and therapy escape; mechanisms underlying EV uptake and cargo utilization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are 50–1000 nm sized, membrane-bound particles released by both eukaryotic and prokaryotic cells and involved in cell-to-cell communication. They can be found in various body fluids, such as blood, urine and saliva, transferring proteins, RNAs, miRNAs and lncRNAs from the originating cells to both neighboring and distant cells.

It is now widely accepted that EVs play a key role in different tumorigenic processes, including cancer proliferation, migration and angiogenesis, as well as tumor drug resistance. Moreover, they are implicated in the interactions between malignant and non-malignant cells in the tumor microenvironment, such as stromal and immune cells. Due to their ubiquitous presence in body fluids and their characteristic of often reflecting the molecular signature of the donor cell, they have recently emerged as promising biomarkers for cancer diagnosis and prognosis. Exciting therapeutic strategies aimed at exploiting EVs as biocompatible drug delivery platforms are also being explored.

This Special Issue focuses on the role of EVs in cancer development, metastasis and therapy resistance. Original papers and review articles on the following topics are welcome: I) mechanisms of EVs’ release and uptake in cancer; II) EV-mediated cross-talk between malignant and non-malignant cells in the tumor microenvironment; III) EVs’ role in the emergence of cancer drug resistance; IV) EVs as a source of biomarkers for cancer diagnosis and prognosis; V) EVs as drug delivery vehicles for cancer treatment.

Dr. Fabrizio Fontana
Dr. Maria Felice Brizzi
Dr. Priya Samuel
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. Cells is an international peer-reviewed open access semimonthly 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 2700 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
  • exosomes
  • microvesicles
  • tumor microenvironment
  • cancer drug resistance
  • cancer diagnosis
  • cancer prognosis
  • biomarkers
  • liquid biopsies
  • cancer therapy

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Published Papers (14 papers)

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Research

Jump to: Review

19 pages, 1994 KiB  
Article
Extracellular Vesicles Isolated from Plasma of Multiple Myeloma Patients Treated with Daratumumab Express CD38, PD-L1, and the Complement Inhibitory Proteins CD55 and CD59
by Kieran Brennan, Katrine F. Iversen, Alfonso Blanco-Fernández, Thomas Lund, Torben Plesner and Margaret M. Mc Gee
Cells 2022, 11(21), 3365; https://doi.org/10.3390/cells11213365 - 25 Oct 2022
Cited by 4 | Viewed by 2817
Abstract
Daratumumab (DARA) has improved the outcome of treatment of multiple myeloma (MM). DARA acts via complement-dependent and -independent mechanisms. Resistance to DARA may result from upregulation of the complement inhibitory proteins CD55 and CD59, downregulation of the DARA target CD38 on myeloma cells [...] Read more.
Daratumumab (DARA) has improved the outcome of treatment of multiple myeloma (MM). DARA acts via complement-dependent and -independent mechanisms. Resistance to DARA may result from upregulation of the complement inhibitory proteins CD55 and CD59, downregulation of the DARA target CD38 on myeloma cells or altered expression of the checkpoint inhibitor ligand programmed death ligand-1 (PD-L1) or other mechanisms. In this study, EVs were isolated from peripheral blood (PB) and bone marrow (BM) from multiple myeloma (MM) patients treated with DARA and PB of healthy controls. EV size and number and the expression of CD38, CD55, CD59 and PD-L1 as well as the EV markers CD9, CD63, CD81, CD147 were determined by flow cytometry. Results reveal that all patient EV samples express CD38, PD-L1, CD55 and CD59. The level of CD55 and CD59 are elevated on MM PB EVs compared with healthy controls, and the level of PD-L1 on MM PB EVs is higher in patients responding to treatment with DARA. CD147, a marker of various aspects of malignant behaviour of cancer cells and a potential target for therapy, was significantly elevated on MM EVs compared with healthy controls. Furthermore, mass spectrometry data suggests that MM PB EVs bind DARA. This study reveals a MM PB and BM EV protein signature that may have diagnostic and prognostic value. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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11 pages, 1947 KiB  
Article
Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes
by Fabrizio Fontana, Martina Anselmi, Emanuela Carollo, Patrizia Sartori, Patrizia Procacci, David Carter and Patrizia Limonta
Cells 2022, 11(15), 2388; https://doi.org/10.3390/cells11152388 - 03 Aug 2022
Cited by 10 | Viewed by 1898
Abstract
Background: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication [...] Read more.
Background: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication has only been focused on soluble factors, although increasing evidence highlights the key role of extracellular vesicles (EVs) in the modulation of tumor progression. Methods and Results: In the present study, we found that EVs derived from 3T3-L1 adipocytes could affect PC3 and DU145 PCa cell traits, inducing increased proliferation, migration and invasion. Furthermore, conditioning of both PCa cell lines with adipocyte-released EVs resulted in lower sensitivity to docetaxel, with reduced phosphatidylserine externalization and decreased caspase 3 and PARP cleavage. In particular, these alterations were paralleled by an Akt/HIF-1α axis-related Warburg effect, characterized by enhanced glucose consumption, lactate release and ATP production. Conclusions: Collectively, these findings demonstrate that EV-mediated crosstalk exists between adipocytes and PCa, driving tumor aggressiveness. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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21 pages, 2592 KiB  
Article
Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma
by Florian Haag, Anjana Manikkam, Daniel Kraft, Caroline Bär, Vanessa Wilke, Aleksander J. Nowak, Jessica Bertrand, Jazan Omari, Maciej Pech, Severin Gylstorff and Borna Relja
Cells 2022, 11(15), 2309; https://doi.org/10.3390/cells11152309 - 27 Jul 2022
Cited by 6 | Viewed by 2434
Abstract
The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. [...] Read more.
The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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23 pages, 8601 KiB  
Article
Comparative Proteomic Profiling of Ectosomes Derived from Thyroid Carcinoma and Normal Thyroid Cells Uncovers Multiple Proteins with Functional Implications in Cancer
by Magdalena Surman, Sylwia Kędracka-Krok, Magdalena Wilczak, Piotr Rybczyński, Urszula Jankowska and Małgorzata Przybyło
Cells 2022, 11(7), 1184; https://doi.org/10.3390/cells11071184 - 31 Mar 2022
Cited by 4 | Viewed by 2400
Abstract
Proteins carried by tumor-derived ectosomes play an important role in cancer progression, and are considered promising diagnostic markers. In the present study, a shotgun nanoLC–MS/MS proteomic approach was applied to profile and compare the protein content of ectosomes released in vitro by normal [...] Read more.
Proteins carried by tumor-derived ectosomes play an important role in cancer progression, and are considered promising diagnostic markers. In the present study, a shotgun nanoLC–MS/MS proteomic approach was applied to profile and compare the protein content of ectosomes released in vitro by normal human thyroid follicular epithelial Nthy-ori 3-1 cells and human anaplastic thyroid carcinoma (TC) 8305C cells. Additionally, the pro-migratory and pro-proliferative effects of Nthy-ori 3-1- and 8305C-derived ectosomes exerted on the recipient cells were assessed in wound closure and Alamar Blue assays. A total of 919 proteins were identified in all replicates of 8305C-derived ectosomes, while Nthy-ori 3-1-derived ectosomes contained a significantly lower number of 420 identified proteins. Qualitative analysis revealed 568 proteins present uniquely in 8305C-derived ectosomes, suggesting their applicability in TC diagnosis and management. In addition, 8305C-derived ectosomes were able to increase the proliferation and motility rates of the recipient cells, likely due to the ectosomal transfer of the identified cancer-promoting molecules. Our description of ectosome protein content and its related functions provides the first insight into the role of ectosomes in TC development and progression. The results also indicate the applicability of some of these ectosomal proteins for further investigation regarding their potential as circulating TC biomarkers. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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19 pages, 2126 KiB  
Article
Extracellular Vesicles from Uterine Aspirates Represent a Promising Source for Screening Markers of Gynecologic Cancers
by Gleb O. Skryabin, Andrey V. Komelkov, Kirill I. Zhordania, Dmitry V. Bagrov, Svetlana V. Vinokurova, Sergey A. Galetsky, Nadezhda V. Elkina, Darya A. Denisova, Adel D. Enikeev and Elena M. Tchevkina
Cells 2022, 11(7), 1064; https://doi.org/10.3390/cells11071064 - 22 Mar 2022
Cited by 8 | Viewed by 2515
Abstract
Extracellular vesicles (EVs), including exosomes, are key factors of intercellular communication, performing both local and distant transfers of bioactive molecules. The increasingly obvious role of EVs in carcinogenesis, similarity of molecular signatures with parental cells, precise selection and high stability of cargo molecules [...] Read more.
Extracellular vesicles (EVs), including exosomes, are key factors of intercellular communication, performing both local and distant transfers of bioactive molecules. The increasingly obvious role of EVs in carcinogenesis, similarity of molecular signatures with parental cells, precise selection and high stability of cargo molecules make exosomes a promising source of liquid biopsy markers for cancer diagnosis. The uterine cavity fluid, unlike blood, urine and other body fluids commonly used to study EVs, is of local origin and therefore enriched in EVs secreted by cells of the female reproductive tract. Here, we show that EVs, including those corresponding to exosomes, could be isolated from individual samples of uterine aspirates (UA) obtained from epithelial ovarian cancer (EOC) patients and healthy donors using the ultracentrifugation technique. First, the conducted profiling of small RNAs (small RNA-seq) from UA-derived EVs demonstrated the presence of non-coding RNA molecules belonging to various classes. The analysis of the miRNA content in EVs from UA performed on a pilot sample revealed significant differences in the expression levels of a number of miRNAs in EVs obtained from EOC patients compared to healthy individuals. The results open up prospects for using UA-derived EVs as a source of markers for the diagnostics of gynecological cancers, including EOC. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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13 pages, 2785 KiB  
Article
FT-IR Spectral Signature of Sensitive and Multidrug-Resistant Osteosarcoma Cell-Derived Extracellular Nanovesicles
by Francesca Perut, Gabriela Graziani, Laura Roncuzzi, Nicoletta Zini, Sofia Avnet and Nicola Baldini
Cells 2022, 11(5), 778; https://doi.org/10.3390/cells11050778 - 23 Feb 2022
Cited by 3 | Viewed by 2146
Abstract
Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, the outcome is unsatisfactory, and multidrug resistance (MDR) is a pivotal process in OS treatment failure. OS-derived extracellular vesicles (EVs) promote drug resistance to chemotherapy and [...] Read more.
Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, the outcome is unsatisfactory, and multidrug resistance (MDR) is a pivotal process in OS treatment failure. OS-derived extracellular vesicles (EVs) promote drug resistance to chemotherapy and target therapy through different mechanisms. The aim of this study was to identify subpopulations of osteosarcoma-EVs by Fourier transform infrared spectroscopy (FT-IR) to define a specific spectral signature for sensitive and multidrug-resistant OS-derived EVs. EVs were isolated from sensitive and MDR OS cells as well as from mesenchymal stem cells by differential centrifugation and ultracentrifugation. EVs size, morphology and protein expression were characterized. FT-IR/ATR of EVs spectra were acquired in the region of 400–4000 cm−1 (resolution 4 cm−1, 128 scans). The FT-IR spectra obtained were consistently different in the EVs compared to cells from which they originate. A specific spectral signature, characterized by a shift and a new band (1601 cm−1), permitted to clearly distinguish EVs isolated by sensitive and multidrug-resistant OS cells. Our data suggest that FT-IR spectroscopy allows to characterize and define a specific spectral signature for sensitive and MDR OS-derived EVs. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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15 pages, 3169 KiB  
Article
A New Approach for Prostate Cancer Diagnosis by miRNA Profiling of Prostate-Derived Plasma Small Extracellular Vesicles
by Lidia Zabegina, Inga Nazarova, Nadezhda Nikiforova, Maria Slyusarenko, Elena Sidina, Margarita Knyazeva, Evgenia Tsyrlina, Sergey Novikov, Sergey Reva and Anastasia Malek
Cells 2021, 10(9), 2372; https://doi.org/10.3390/cells10092372 - 09 Sep 2021
Cited by 16 | Viewed by 3979
Abstract
Vesicular miRNA has emerged as a promising marker for various types of cancer, including prostate cancer (PC). In the advanced stage of PC, the cancer-cell-derived small extracellular vesicles (SEVs) may constitute a significant portion of circulating vesicles and may mediate a detectable change [...] Read more.
Vesicular miRNA has emerged as a promising marker for various types of cancer, including prostate cancer (PC). In the advanced stage of PC, the cancer-cell-derived small extracellular vesicles (SEVs) may constitute a significant portion of circulating vesicles and may mediate a detectable change in the plasma vesicular miRNA profile. However, SEVs secreted by small tumor in the prostate gland constitute a tiny fraction of circulating vesicles and cause undetectable miRNA pattern changes. Thus, the isolation and miRNA profiling of a specific prostate-derived fraction of SEVs can improve the diagnostic potency of the methods based on vesicular miRNA analysis. Prostate-specific membrane antigen (PSMA) was selected as a marker of prostate-derived SEVs. Super-paramagnetic beads (SPMBs) were functionalized by PSMA-binding DNA aptamer (PSMA–Apt) via a click reaction. The efficacy of SPMB–PSMA–Apt complex formation and PSMA(+)SEVs capture were assayed by flow cytometry. miRNA was isolated from the total population of SEVs and PSMA(+)SEVs of PC patients (n = 55) and healthy donors (n = 30). Four PC-related miRNAs (miR-145, miR-451a, miR-143, and miR-221) were assayed by RT-PCR. The click chemistry allowed fixing DNA aptamers onto the surface of SPMB with an efficacy of up to 89.9%. The developed method more effectively isolates PSMA(+)SEVs than relevant antibody-based technology. The analysis of PC-related miRNA in the fraction of PSMA(+)SEVs was more sensitive and revealed distinct diagnostic potency (AUC: miR-145, 0.76; miR-221, 0.7; miR-451a, 0.65; and miR-141, 0.64) than analysis of the total SEV population. Thus, isolation of prostate-specific SEVs followed by analysis of vesicular miRNA might be a promising PC diagnosis method. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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16 pages, 2071 KiB  
Article
Proteomic Analysis of Circulating Extracellular Vesicles Identifies Potential Biomarkers for Lymph Node Metastasis in Oral Tongue Squamous Cell Carcinoma
by Xinyu Qu, Thomas C. N. Leung, Sai-Ming Ngai, Sau-Na Tsai, Abhimanyu Thakur, Wing-Kar Li, Youngjin Lee, Leanne Leung, Tung-Him Ng, Judy Yam, Linlin Lan, Eric H. L. Lau, Eddy W. Y. Wong, Jason Y. K. Chan and Katie Meehan
Cells 2021, 10(9), 2179; https://doi.org/10.3390/cells10092179 - 24 Aug 2021
Cited by 11 | Viewed by 3663
Abstract
Lymph node metastasis is the most reliable indicator of a poor prognosis for patients with oral tongue cancers. Currently, there are no biomarkers to predict whether a cancer will spread in the future if it has not already spread at the time of [...] Read more.
Lymph node metastasis is the most reliable indicator of a poor prognosis for patients with oral tongue cancers. Currently, there are no biomarkers to predict whether a cancer will spread in the future if it has not already spread at the time of diagnosis. The aim of this study was to quantitatively profile the proteomes of extracellular vesicles (EVs) isolated from blood samples taken from patients with oral tongue squamous cell carcinoma with and without lymph node involvement and non-cancer controls. EVs were enriched using size exclusion chromatography (SEC) from pooled plasma samples of patients with non-nodal and nodal oral tongue squamous cell carcinoma (OTSCC) and non-cancer controls. Protein cargo was quantitatively profiled using isobaric labelling (iTRAQ) and two-dimensional high-performance liquid chromatography followed by tandem mass spectrometry. We identified 208 EV associated proteins and, after filtering, generated a short list of 136 proteins. Over 85% of the EV-associated proteins were associated with the GO cellular compartment term “extracellular exosome”. Comparisons between non-cancer controls and oral tongue squamous cell carcinoma with and without lymph node involvement revealed 43 unique candidate EV-associated proteins with deregulated expression patterns. The shortlisted EV associated proteins described here may be useful discriminatory biomarkers for differentiating OTSCC with and without nodal disease or non-cancer controls. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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Review

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17 pages, 2075 KiB  
Review
Small Extracellular Vesicles: Key Forces Mediating the Development and Metastasis of Colorectal Cancer
by Wenjie Zhang, Xiaoxue Hu and Zhengting Jiang
Cells 2022, 11(11), 1780; https://doi.org/10.3390/cells11111780 - 29 May 2022
Cited by 6 | Viewed by 2167
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence and mortality rates have been increasing annually in recent years. A variety of different small extracellular vesicles (sEVs) are important mediators of intercellular communication and have an important role in [...] Read more.
Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence and mortality rates have been increasing annually in recent years. A variety of different small extracellular vesicles (sEVs) are important mediators of intercellular communication and have an important role in tumor metastasis and progression. The development and metastasis of CRC are closely linked to tumor-cell-derived sEVs, non-tumor-cell-derived sEVs, and intestinal-microbiota-derived sEVs. Numerous studies have shown that the tumor microenvironment (TME) is a key component in the regulation of CRC proliferation, development, and metastasis. These sEVs can create a TME conducive to CRC growth and metastasis by forming an immunosuppressive microenvironment, remodeling the extracellular matrix, and promoting tumor cell metabolism. Therefore, in this paper, we review the role of different types of sEVs in colorectal cancer development and metastasis. Furthermore, based on the properties of sEVs, we further discuss the use of sEVs as early biomarkers for colorectal cancer diagnosis and the potential for their use in the treatment of CRC. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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33 pages, 484 KiB  
Review
Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies
by Alessandro Allegra, Claudia Petrarca, Mario Di Gioacchino, Marco Casciaro, Caterina Musolino and Sebastiano Gangemi
Cells 2022, 11(7), 1128; https://doi.org/10.3390/cells11071128 - 27 Mar 2022
Cited by 8 | Viewed by 3376
Abstract
Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit [...] Read more.
Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
27 pages, 1754 KiB  
Review
T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy
by Victor Calvo and Manuel Izquierdo
Cells 2022, 11(5), 790; https://doi.org/10.3390/cells11050790 - 24 Feb 2022
Cited by 18 | Viewed by 6056
Abstract
Extracellular vesicles (EV) are a very diverse group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular exchange, both nearby and systemically, since they induce signals and transmit their cargo (proteins, lipids, miRNAs) to other cells, [...] Read more.
Extracellular vesicles (EV) are a very diverse group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular exchange, both nearby and systemically, since they induce signals and transmit their cargo (proteins, lipids, miRNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. However, cell surface receptor-induced EV release is limited to cells from the immune system, including T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptors for antigen and several bioactive molecules, including proapoptotic proteins. These EV are specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we examine the generation of EV by T lymphocytes and CAR-T cells and some potential therapeutic approaches of these EV. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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40 pages, 22909 KiB  
Review
Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects
by Sadaf Jahan, Shouvik Mukherjee, Shaheen Ali, Urvashi Bhardwaj, Ranjay Kumar Choudhary, Santhanaraj Balakrishnan, Asma Naseem, Shabir Ahmad Mir, Saeed Banawas, Mohammed Alaidarous, Hadeel Alyenbaawi, Danish Iqbal and Arif Jamal Siddiqui
Cells 2022, 11(3), 490; https://doi.org/10.3390/cells11030490 - 31 Jan 2022
Cited by 19 | Viewed by 5083
Abstract
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) [...] Read more.
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs’ role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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23 pages, 8913 KiB  
Review
Emerging Role of Extracellular Vesicles and Cellular Communication in Metastasis
by Aisling Forder, Chi-Yun Hsing, Jessica Trejo Vazquez and Cathie Garnis
Cells 2021, 10(12), 3429; https://doi.org/10.3390/cells10123429 - 06 Dec 2021
Cited by 25 | Viewed by 3936
Abstract
Communication between cancer cells and the surrounding stromal cells of the tumor microenvironment (TME) plays a key role in promoting metastasis, which is the major cause of cancer death. Small membrane-bound particles called extracellular vesicles (EVs) are released from both cancer and stromal [...] Read more.
Communication between cancer cells and the surrounding stromal cells of the tumor microenvironment (TME) plays a key role in promoting metastasis, which is the major cause of cancer death. Small membrane-bound particles called extracellular vesicles (EVs) are released from both cancer and stromal cells and have a key role in mediating this communication through transport of cargo such as various RNA species (mRNA, miRNA, lncRNA), proteins, and lipids. Tumor-secreted EVs have been observed to induce a pro-tumorigenic phenotype in non-malignant cells of the stroma, including fibroblasts, endothelial cells, and local immune cells. These cancer-associated cells then drive metastasis by mechanisms such as increasing the invasiveness of cancer cells, facilitating angiogenesis, and promoting the formation of the pre-metastatic niche. This review will cover the role of EV-mediated signaling in the TME during metastasis and highlight the therapeutic potential of targeting these pathways to develop biomarkers and novel treatment strategies. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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24 pages, 1039 KiB  
Review
Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies
by Alessandro Allegra, Mario Di Gioacchino, Alessandro Tonacci, Claudia Petrarca, Caterina Musolino and Sebastiano Gangemi
Cells 2021, 10(11), 2865; https://doi.org/10.3390/cells10112865 - 24 Oct 2021
Cited by 13 | Viewed by 3539
Abstract
Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension [...] Read more.
Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Modulators of Cancer Initiation, Progression and Therapy Resistance)
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