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Extracellular Vesicles in Cancer Progression and Drug Resistance

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 October 2019) | Viewed by 48608

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Special Issue Editor

Dr. M. Helena Vasconcelos

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Guest Editor

1. FFUP – Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, Potugal
2. i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Interests: cancer drug resistance; cancer multidrug resistance; intercellular transfer of drug resistance mediated by Extracellular Vesicles (EVs); new approaches to overcome drug resistance; drug-efflux pumps; escape from apoptosis; autophagy; metabolic alterations associated with drug resistance; tumour-microenvironment interactions; cancer stem cells; microRNAs; biomarkers of minimal residual disease and of drug resistance
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Special Issue Information

Dear Colleagues,

The release of extracellular vesicles (EVs) by cancer cells has tremendous impact in cancer progression, from the proliferation of cancer cells to ECM degradation, angiogenesis, metastasis, escape from immune response, or drug resistance. This is as a result of the horizontal transfer of the EV’s cargo (such as proteins, miRNAs, or long noncoding RNAs) from the donor cells to recipient cells. EVs are also responsible for drug efflux from the donor cells, reducing the intracellular drug concentrations to sublethal ones.

Remarkably, the presence of EVs released by tumour cells in the biological fluids of cancer patients is allowing their study as a possible source of biomarkers in liquid biopsies, for diagnosis or prognosis purposes.

This Special Issue of Cancers aims to collect review and original research articles on the impact of EVs on cancer progression and drug resistance, and also on cancer patient’s diagnosis and prognosis. Topics may include, but are not exclusively limited to, studying the following: (i) role of EVs in the various hallmarks of cancer; (ii) cargo of EVs and their horizontal transfer; (iii) mechanisms of release of EVs by donor cells, and their uptake by recipient cells; (iv) search for biomarkers of cancer diagnosis or prognosis in liquid biopsies.

Prof. Dr. M. Helena Vasconcelos
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. Cancers 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 2900 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
Cancer progression
Hallmarks of cancer
Cancer drug resistance
Biomarkers of cancer diagnosis
Biomarkers of cancer prognosis
Biomarkers of minimal residual disease
Liquid biopsies

Published Papers (10 papers)

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Research

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16 pages, 1811 KiB

Open AccessArticle

Extracellular Vesicle lincRNA-p21 Expression in Tumor-Draining Pulmonary Vein Defines Prognosis in NSCLC and Modulates Endothelial Cell Behavior

by Joan J. Castellano, Ramon M. Marrades, Laureano Molins, Nuria Viñolas, Jorge Moises, Jordi Canals, Bing Han, Yan Li, Daniel Martinez, Mariano Monzó and Alfons Navarro

Cancers 2020, 12(3), 734; https://doi.org/10.3390/cancers12030734 - 20 Mar 2020

Cited by 36 | Viewed by 3898

Abstract

Hypoxia-induced upregulation of lincRNA-p21 in tumor tissue was previously shown by our group to be related to poor prognosis in resected non-small cell lung cancer (NSCLC) patients. In the present study, we have evaluated the presence of lincRNA-p21 in extracellular vesicles (EVs) from NSCLC patients and assessed its potential as a prognostic biomarker. High EV lincRNA-p21 levels in blood from the tumor-draining vein were associated with shorter time to relapse and shorter overall survival. Moreover, the multivariate analysis identified high lincRNA-p21 levels as an independent prognostic marker. In addition, lincRNA-p21 was overexpressed in H23 and HCC44 NSCLC cell lines and their derived EVs under hypoxic conditions. Functional assays using human umbilical vein endothelial cells (HUVECs) showed that tumor-derived EVs enriched in lincRNA-p21 affected endothelial cells by promoting tube formation and enhancing tumor cell adhesion to endothelial cells. Additionally, the analysis of selected EV microRNAs related to angiogenesis and metastasis showed that the microRNAs correlated with EV lincRNA-p21 levels in both patients and cell lines. Finally, EV co-culture with HUVEC cells increased the expression of microRNAs and genes related to endothelial cell activation. In conclusion, EV lincRNA-p21 acts as a novel prognosis marker in resected NSCLC patients, promoting angiogenesis and metastasis. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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23 pages, 8360 KiB

Open AccessArticle

CD147 Promotes Cell Small Extracellular Vesicles Release during Colon Cancer Stem Cells Differentiation and Triggers Cellular Changes in Recipient Cells

by Donatella Lucchetti, Filomena Colella, Luigi Perelli, Claudio Ricciardi-Tenore, Federica Calapà, Micol E. Fiori, Federica Carbone, Ruggero De Maria and Alessandro Sgambato

Cancers 2020, 12(2), 260; https://doi.org/10.3390/cancers12020260 - 21 Jan 2020

Cited by 11 | Viewed by 3697

Abstract

Cancer cells secrete small extracellular vesicles (sEVs) that are involved in the remodeling of tumor microenvironment (TME) and can promote tumor progression. The role of sEVs and their molecular key players in colon cancer stem cells differentiation are poorly understood. This study aimed to analyze the role and content of sEVs released during the differentiation of colorectal cancer stem cells. Here we show that sEVs secretion during colon cancer stem cells differentiation is partially controlled by CD147, a well-known player involved in colon cancer tumorigenesis. CD147 + sEVs activate a signaling cascade in recipient cells inducing molecular invasive features in colon cancer cells. CD147 knockdown as well as anti-CD147 antibodies impaired sEVs release and downstream effects on recipient cells and blocking multivesicular body maturation prevented sEVs release during the differentiation. Our findings reveal a functional role of CD147 in promoting sEVs release during the differentiation of colon cancer stem cells and in triggering cellular changes in recipient cells. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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22 pages, 3801 KiB

Open AccessArticle

Deep Sequencing Analysis Reveals Distinctive Non-Coding RNAs When Comparing Tumor Multidrug-Resistant Cells and Extracellular Vesicles with Drug-Sensitive Counterparts

by Diana Sousa, Rune Matthiesen, Raquel T. Lima and M. Helena Vasconcelos

Cancers 2020, 12(1), 200; https://doi.org/10.3390/cancers12010200 - 14 Jan 2020

Cited by 14 | Viewed by 3448

Abstract

Multidrug resistance (MDR) is one of the main limitations of cancer treatment. The overexpression of drug-efflux pumps, such as P-glycoprotein (P-gp), is a major cause of MDR. Importantly, different studies have shown that extracellular vesicles (EVs) participate in the communication between MDR cells and drug-sensitive counterparts, promoting dissemination of the MDR phenotype. In the present work, we aimed to identify RNA species present in MDR cells and in EVs released by those cells, which may be associated with the MDR phenotype. The RNA content from two pairs (leukemia and lung cancer) of MDR (P-gp overexpressing) cells and their drug-sensitive counterparts, as well as from their EVs, was analyzed by deep sequencing. Our results showed distinctive transcripts for MDR cells and their EVs, when compared with their drug-sensitive counterparts. Remarkably, two pseudogenes (a novel pseudogene and RNA 5.8S ribosomal pseudogene 2) were found to be increased in EVs released by MDR cells in both leukemia and lung cancer models. Moreover, six miRs (miR-204-5p, miR-139-5p, miR-29c-5p, miR-551b-3p, miR-29b-2-5p, and miR-204-3p) exhibited altered levels in lung cancer MDR cells and their EVs. This study provides insights into the contribution of EVs to MDR. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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14 pages, 3062 KiB

Open AccessArticle

Extracellular Vesicles-Based Biomarkers Represent a Promising Liquid Biopsy in Endometrial Cancer

by Carolina Herrero, Alexandre de la Fuente, Carlos Casas-Arozamena, Victor Sebastian, Martin Prieto, Manuel Arruebo, Alicia Abalo, Eva Colás, Gema Moreno-Bueno, Antonio Gil-Moreno, Ana Vilar, Juan Cueva, Miguel Abal and Laura Muinelo-Romay

Cancers 2019, 11(12), 2000; https://doi.org/10.3390/cancers11122000 - 12 Dec 2019

Cited by 30 | Viewed by 4533

Abstract

Tumor-derived extracellular vesicles (EVs) are secreted in large amounts into biological fluids of cancer patients. The analysis of EVs cargoes has been associated with patient´s outcome and response to therapy. However, current technologies for EVs isolation are tedious and low cost-efficient for routine clinical implementation. To explore the clinical value of circulating EVs analysis we attempted a proof-of-concept in endometrial cancer (EC) with ExoGAG, an easy to use and highly efficient new technology to enrich EVs. Technical performance was first evaluated using EVs secreted by Hec1A cells. Then, the clinical value of this strategy was questioned by analyzing the levels of two well-known tissue biomarkers in EC, L1 cell adhesion molecule (L1CAM) and Annexin A2 (ANXA2), in EVs purified from plasma in a cohort of 41 EC patients and 20 healthy controls. The results demonstrated the specific content of ANXA2 in the purified EVs fraction, with an accurate sensitivity and specificity for EC diagnosis. Importantly, high ANXA2 levels in circulating EVs were associated with high risk of recurrence and non-endometrioid histology suggesting a potential value as a prognostic biomarker in EC. These results also confirmed ExoGAG technology as a robust technique for the clinical implementation of circulating EVs analyses. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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17 pages, 3320 KiB

Open AccessArticle

Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles

by Xin-Hui Khoo, Ian C. Paterson, Bey-Hing Goh and Wai-Leng Lee

Cancers 2019, 11(8), 1166; https://doi.org/10.3390/cancers11081166 - 14 Aug 2019

Cited by 51 | Viewed by 5669

Abstract

Drug resistance remains a severe problem in most chemotherapy regimes. Recently, it has been suggested that cancer cell-derived extracellular vesicles (EVs) could mediate drug resistance. In this study, the role of EVs in mediating the response of oral squamous cell carcinoma (OSCC) cells to cisplatin was investigated. We isolated and characterized EVs from OSCC cell lines showing differential sensitivities to cisplatin. Increased EV production was observed in both de novo (H314) and adaptive (H103/cisD2) resistant lines compared to sensitive H103 cells. The protein profiles of these EVs were then analyzed. Differences in the proteome of EVs secreted by H103 and H103/cisD2 indicated that adaptation to cisplatin treatment caused significant changes in the secreted nanovesicles. Intriguingly, both resistant H103/cisD2 and H314 cells shared a highly similar EV protein profile including downregulation of the metal ion transporter, ATP1B3, in the EVs implicating altered drug delivery. ICP-MS analysis revealed that less cisplatin accumulated in the resistant cells, but higher levels were detected in their EVs. Therefore, we inhibited EV secretion from the cells using a proton pump inhibitor and observed an increased drug sensitivity in cisplatin-resistant H314 cells. This finding suggests that control of EV secretion could be a potential strategy to enhance the efficacy of cancer treatment. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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14 pages, 2216 KiB

Open AccessArticle

Vesicular-Bound HLA-G as a Predictive Marker for Disease Progression in Epithelial Ovarian Cancer

by Esther Schwich, Vera Rebmann, Peter A. Horn, Alexander A. Celik, Christina Bade-Döding, Rainer Kimmig, Sabine Kasimir-Bauer and Paul Buderath

Cancers 2019, 11(8), 1106; https://doi.org/10.3390/cancers11081106 - 02 Aug 2019

Cited by 24 | Viewed by 3335

Abstract

Extracellular vesicles (EV) and their tumor-supporting cargos provide a promising translational potential in liquid biopsies for risk assessment of epithelial ovarian cancer (EOC) patients frequently relapsing, despite initial complete therapy responses. As the immune checkpoint molecule HLA-G, which is operative in immune-escape, can be released by EV, we evaluate the abundance of EV and its vesicular-bound amount of HLA-G (HLA-G_EV) as a biomarker in EOC. After enrichment of EV from plasma samples, we determined the EV particle number and amount of HLA-G_EV by nanoparticle tracking analysis or ELISA. The association of results with the clinical status/outcome revealed that both, EV particle number and HLA-G_EV were significantly elevated in EOC patients, compared to healthy females. However, elevated levels of HLA-G_EV, but not EV numbers, were exclusively associated with a disadvantageous clinical status/outcome, including residual tumor, presence of circulating tumor cells, and disease progression. High HLA-G_EV status was an independent predictor of progression, besides residual tumor burden and platinum-sensitivity. Especially among patients without residual tumor burden or with platinum-sensitivity, HLA-G_EV identified patients with high risk of progression. Thus, this study highlights HLA-G_EV as a potential novel biomarker for risk assessment of EOC patients with a rather beneficial prognosis defined by platinum-sensitivity or lack of residual tumor burden. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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Review

Jump to: Research

19 pages, 1331 KiB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity

by Donatella Lucchetti, Claudio Ricciardi Tenore, Filomena Colella and Alessandro Sgambato

Cancers 2020, 12(1), 171; https://doi.org/10.3390/cancers12010171 - 10 Jan 2020

Cited by 40 | Viewed by 5598

Abstract

A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is not peculiar to cancer cells but reflects the characteristics of the tumor microenvironment. Recently, it has been shown that extracellular vesicles are involved in the metabolic switch occurring in cancer and tumor-stroma cells. Moreover, in an immune system, the metabolic programs of different cell subsets are distinctly associated with their immunological function, and extracellular vesicles could be a key factor in the shift of cell fate modulating cancer immunity. Indeed, during tumor progression, tumor-associated immune cells and fibroblasts acquire a tumor-supportive and anti-inflammatory phenotype due to their interaction with tumor cells and several findings suggest a role of extracellular vesicles in this phenomenon. This review aims to collect all the available evidence so far obtained on the role of extracellular vesicles in the modulation of cell metabolism and immunity. Moreover, we discuss the possibility for extracellular vesicles of being involved in drug resistance mechanisms, cancer progression and metastasis by inducing immune-metabolic effects on surrounding cells. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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20 pages, 1306 KiB

Open AccessReview

Extracellular Vesicles in Non-Small-Cell Lung Cancer: Functional Role and Involvement in Resistance to Targeted Treatment and Immunotherapy

by Luigi Pasini and Paola Ulivi

Cancers 2020, 12(1), 40; https://doi.org/10.3390/cancers12010040 - 21 Dec 2019

Cited by 21 | Viewed by 4034

Abstract

Targeted and immunological therapies have become the gold standard for a large portion of non-small cell lung cancer (NSCLC) patients by improving significantly clinical prognosis. However, resistance mechanisms inevitably develop after a first response, and almost all patients undergo progression. The knowledge of such a resistance mechanism is crucial to improving the efficacy of therapies. So far, monitoring therapy responses through liquid biopsy has been carried out mainly in terms of circulating tumor (ctDNA) analysis. However, other particles of tumor origin, such as extracellular vehicles (EVs) represent an emerging tool for the studying and monitoring of resistance mechanisms. EVs are now considered to be ubiquitous mediators of cell-to-cell communication, allowing cells to exchange biologically active cargoes that vary in response to the microenvironment and include proteins, metabolites, RNA species, and nucleic acids. Novel findings on the biogenesis and fate of these vesicles reveal their fundamental role in cancer progression, with foreseeable and not-far-to-come clinical applications in NSCLC. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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19 pages, 1608 KiB

Open AccessReview

Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

by Flora Guerra and Cecilia Bucci

Cancers 2019, 11(8), 1096; https://doi.org/10.3390/cancers11081096 - 01 Aug 2019

Cited by 31 | Viewed by 7437

Abstract

RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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23 pages, 1431 KiB

Open AccessReview

The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment, Metastasis and Drug Resistance in Colorectal Cancer

by Kodappully S. Siveen, Afsheen Raza, Eiman I. Ahmed, Abdul Q. Khan, Kirti S. Prabhu, Shilpa Kuttikrishnan, Jericha M. Mateo, Hatem Zayed, Kakil Rasul, Fouad Azizi, Said Dermime, Martin Steinhoff and Shahab Uddin

Cancers 2019, 11(6), 746; https://doi.org/10.3390/cancers11060746 - 29 May 2019

Cited by 43 | Viewed by 6197

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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