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Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 16177

Special Issue Editors

Centre for Integrative Biology, University of Trento, Via Sommarive, 9, 38123, Povo Trento, Italy
Interests: cancer; Zebrafish; cancer metabolism; telomere maintenance; melanoma; brain tumor; apoptosis; cell-cell interactions; exosomes; cell migration; cell cycle
Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy
Interests: extracellular vesicles; RNA-binding proteins; liquid biopsy; cancer; biomarkers; ultrasensitive assays; nanocarriers; high-throughput screening

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs), representing an intercellular communication system that is highly enhanced in cancer, continue to attract formidable interest from a wide range of scientists for their tremendous potential to allow discoveries ranging from basic biology to innovative therapeutic approaches.

We are still far away from a full understanding of the roles of EVs in cancer progression, as we have not yet developed their potential as diagnostic or prognostic tools, and we have only glimpsed their value as precision delivery vehicles to transport drugs and non-coding RNAs to target cells.

With this Special Issue, we aim to attract reports that take innovative approaches or express novel views on the multifaceted world of EVs in cancer biology, progression and therapy.

Original papers and review articles that focus on the latest advances in EV studies are welcome. Key areas that will be covered include the following:

  • The use of model systems to study the biology of EVs in cancer and exploit them for diagnostic, prognostic and therapeutic approaches;
  • The relations between the cell of origin and their targets;
  • EVs as a source of biomarkers in liquid biopsy;
  • The role of EVs in inflammation and in shaping the tumor microenvironment;
  • Specific cargos and their role in recipient cells and cancer progression;
  • EV engineering for targeted therapy.

Dr. Maria Caterina Mione
Dr. Vito Giuseppe D'Agostino
Guest Editors

Manuscript Submission Information

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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

  • extracellular vesicles
  • model systems
  • intercellular communication
  • cancer biomarker
  • non-coding RNA in cancer
  • molecular diagnostics
  • liquid biopsies
  • biomarkers
  • molecular engineering
  • targeted therapies

Published Papers (6 papers)

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Research

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18 pages, 3693 KiB  
Article
Proteomic Profiling of Extracellular Vesicles Released by Leptin-Treated Breast Cancer Cells: A Potential Role in Cancer Metabolism
by Luca Gelsomino, Ines Barone, Amanda Caruso, Francesca Giordano, Matteo Brindisi, Giovanna Morello, Felice Maria Accattatis, Salvatore Panza, Anna Rita Cappello, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano and Cinzia Giordano
Int. J. Mol. Sci. 2022, 23(21), 12941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112941 - 26 Oct 2022
Cited by 5 | Viewed by 2016
Abstract
Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity [...] Read more.
Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese patients. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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19 pages, 5037 KiB  
Article
Characterization of the MicroRNA Cargo of Extracellular Vesicles Isolated from a Pulmonary Tumor-Draining Vein Identifies miR-203a-3p as a Relapse Biomarker for Resected Non-Small Cell Lung Cancer
by Bing Han, Laureano Molins, Yangyi He, Nuria Viñolas, David Sánchez-Lorente, Marc Boada, Angela Guirao, Tania Díaz, Daniel Martinez, Jose Ramirez, Jorge Moisés, Melissa Acosta-Plasencia, Mariano Monzo, Ramón M. Marrades and Alfons Navarro
Int. J. Mol. Sci. 2022, 23(13), 7138; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137138 - 27 Jun 2022
Cited by 8 | Viewed by 2243
Abstract
In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the [...] Read more.
In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV-miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17-miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV-miR-203a-3p) was chosen for further validation. Pulmonary TDV EV-miR-203a-3p was studied by qRT-PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV-miR-203a-3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV-miR-203a-3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV-miR-203a-3p was an independent, predictive and prognostic post-surgical relapse biomarker. In conclusion, pulmonary TDV EV-miR-203a-3p is a promising new relapse biomarker for resected NSCLC patients. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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19 pages, 7401 KiB  
Article
Zebrafish Melanoma-Derived Interstitial EVs Are Carriers of ncRNAs That Induce Inflammation
by Valentina Biagini, Federica Busi, Viviana Anelli, Emanuela Kerschbamer, Marta Baghini, Elena Gurrieri, Michela Notarangelo, Isabella Pesce, Guillaume van Niel, Vito G. D’Agostino and Marina Mione
Int. J. Mol. Sci. 2022, 23(10), 5510; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105510 - 14 May 2022
Cited by 3 | Viewed by 3091
Abstract
Extracellular vesicles (EVs) are membranous particles released by all cell types. Their role as functional carrier of bioactive molecules is boosted by cells that actively secrete them in biological fluids or in the intercellular space (interstitial EVs, iEVs). Here we have optimised a [...] Read more.
Extracellular vesicles (EVs) are membranous particles released by all cell types. Their role as functional carrier of bioactive molecules is boosted by cells that actively secrete them in biological fluids or in the intercellular space (interstitial EVs, iEVs). Here we have optimised a method for the isolation and characterization of zebrafish iEVs from whole melanoma tissues. Zebrafish melanoma iEVs are around 140 nm in diameter, as determined by nanoparticle tracking and transmission electron microscopy (TEM) analysis. Western blot analysis shows enrichment for CD63 and Alix in the iEV fraction, but not in melanoma cell lysates. Super resolution and confocal microscopy reveal that purified zebrafish iEVs are green fluorescent protein positive (GFP+), indicating that they integrate the oncogene GFP-HRASV12G used to induce melanoma in this model within their vesicular membrane or luminal content. Analysis of RNA-Seq data found 118 non-coding (nc)RNAs differentially distributed between zebrafish melanoma and their iEVs, with only 17 of them being selectively enriched in iEVs. Among these, the RNA components of RNAses P and MRP, which process ribosomal RNA precursors, mitochondrial RNAs, and some mRNAs, were enriched in zebrafish and human melanoma EVs, but not in iEVs extracted from brain tumours. We found that melanoma iEVs induce an inflammatory response when injected in larvae, with increased expression of interferon responsive genes, and this effect is reproduced by MRP- or P-RNAs injected into circulation. This suggests that zebrafish melanoma iEVs are a source of MRP- and P-RNAs that can trigger inflammation in cells of the innate immune system. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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15 pages, 2514 KiB  
Article
CD44 Expression Intensity Marks Colorectal Cancer Cell Subpopulations with Different Extracellular Vesicle Release Capacity
by Andrea Kelemen, Idan Carmi, Iván Seress, Péter Lőrincz, Tamás Tölgyes, Kristóf Dede, Attila Bursics, Edit I. Buzás and Zoltán Wiener
Int. J. Mol. Sci. 2022, 23(4), 2180; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042180 - 16 Feb 2022
Cited by 6 | Viewed by 2683
Abstract
Extracellular vesicles (EV) are released by virtually all cells and they transport biologically important molecules from the release site to target cells. Colorectal cancer (CRC) is a leading cause of cancer-related death cases, thus, it represents a major health issue. Although the EV [...] Read more.
Extracellular vesicles (EV) are released by virtually all cells and they transport biologically important molecules from the release site to target cells. Colorectal cancer (CRC) is a leading cause of cancer-related death cases, thus, it represents a major health issue. Although the EV cargo may reflect the molecular composition of the releasing cells and thus, EVs may hold a great promise for tumor diagnostics, the impact of intratumoral heterogeneity on the intensity of EV release is still largely unknown. By using CRC patient-derived organoids that maintain the cellular and molecular heterogeneity of the original epithelial tumor tissue, we proved that CD44high cells produce more organoids with a higher proliferation intensity, as compared to CD44low cells. Interestingly, we detected an increased EV release by CD44high CRC cells. In addition, we found that the miRNA cargos of CD44high and CD44low cell derived EVs largely overlapped and only four miRNAs were specific for one of the above subpopulations. We observed that EVs released by CD44high cells induced the proliferation and activation of colon fibroblasts more strongly than CD44low cells. However, this effect was due to the higher EV number rather than to the miRNA cargo of EVs. Collectively, we identified CRC subpopulations with different EV releasing capabilities and we proved that CRC cell-released EVs have a miRNA-independent effect on fibroblast proliferation and activation. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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Review

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13 pages, 629 KiB  
Review
Microglial Extracellular Vesicles as Modulators of Brain Microenvironment in Glioma
by Myriam Catalano, Carmela Serpe and Cristina Limatola
Int. J. Mol. Sci. 2022, 23(21), 13165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113165 - 29 Oct 2022
Cited by 4 | Viewed by 1719
Abstract
Microglial cells represent the resident immune elements of the central nervous system, where they exert constant monitoring and contribute to preserving neuronal activity and function. In the context of glioblastoma (GBM), a common type of tumor originating in the brain, microglial cells deeply [...] Read more.
Microglial cells represent the resident immune elements of the central nervous system, where they exert constant monitoring and contribute to preserving neuronal activity and function. In the context of glioblastoma (GBM), a common type of tumor originating in the brain, microglial cells deeply modify their phenotype, lose their homeostatic functions, invade the tumoral mass and support the growth and further invasion of the tumoral cells into the surrounding brain parenchyma. These modifications are, at least in part, induced by bidirectional communication among microglial and tumoral cells through the release of soluble molecules and extracellular vesicles (EVs). EVs produced by GBM and microglial cells transfer different kinds of biological information to receiving cells, deeply modifying their phenotype and activity and could represent important diagnostic markers and therapeutic targets. Recent evidence demonstrates that in GBM, microglial-derived EVs contribute to the immune suppression of the tumor microenvironment (TME), thus favoring GBM immune escape. In this review, we report the current knowledge on EV formation, biogenesis, cargo and functions, with a focus on the effects of microglia-derived EVs in GBM. What clearly emerges from this analysis is that we are at the beginning of a full understanding of the complete picture of the biological effects of microglial-derived EVs and that further investigations using multidisciplinary approaches are necessary to validate their use in GBM diagnosis and therapy. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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15 pages, 707 KiB  
Review
Extracellular Vesicles as Biomarkers Carriers in Bladder Cancer: Diagnosis, Surveillance, and Treatment
by Natalia Georgantzoglou, Alexandros Pergaris, Christos Masaoutis and Stamatios Theocharis
Int. J. Mol. Sci. 2021, 22(5), 2744; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052744 - 09 Mar 2021
Cited by 23 | Viewed by 3393
Abstract
Exosomes are extracellular vesicles, enriched in biomolecular cargo consisting of nucleic acids, proteins, and lipids, which take part in intercellular communication and play a crucial role in both physiologic functions and oncogenesis. Bladder cancer is the most common urinary malignancy and its incidence [...] Read more.
Exosomes are extracellular vesicles, enriched in biomolecular cargo consisting of nucleic acids, proteins, and lipids, which take part in intercellular communication and play a crucial role in both physiologic functions and oncogenesis. Bladder cancer is the most common urinary malignancy and its incidence is steadily rising in developed countries. Despite the high five-year survival in patients diagnosed at early disease stage, survival substantially drops in patients with muscle-invasive or metastatic disease. Therefore, early detection of primary disease as well as recurrence is of paramount importance. The role that exosomal biomarkers could play in bladder cancer patient diagnosis and surveillance, as well as their potential therapeutic applications, has not been extensively studied in this malignancy. In the present review, we summarize all relevant data obtained so far from cell lines, animal models, and patient biofluids and tissues. Current literature suggests that urine is a rich source of extracellular vesicle-derived biomarkers, compared with blood and bladder tissue samples, with potential applications in bladder cancer management. Further studies improving sample collection procedures and optimizing purification and analytical methods should augment bladder cancer diagnostic, prognostic, and therapeutic input of extracellular vesicles biomarkers in the future. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Diagnosis, Progression and Therapy)
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