Cell-Cell Communication and Extracellular Vesicles in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 20641

Special Issue Editors

Department of Medicine and Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Interests: cell death and proliferation; signal transduction; inflammation; fibrosis; and kidney injury and repair
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Interests: cell-cell communication; Orai channels
Department of Medicine, Division of Nephrology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Interests: cell-cell communication; integrin signal pathway; NF-κB signaling pathway

Special Issue Information

Dear Colleague,

Cell–cell communication, either through direct contact or indirectly, is critical for multiple cellular processes, such as proliferation, survival, differentiation, and transdifferentiation, and plays a fundamental role in maintaining the integrity of tissue structure and the cellular environment. Extracellular vesicles (EVs) are a group of nanosized lipid-bound vesicles derived from various cellular origins that play a key role in cell–cell communication. EV-mediated cell–cell communication is involved in multiple processes of tumorigenesis and metastasis. It not only affects tumor growth, metabolism, and survival but also facilitates the surrounding or distant non-tumor cells to form a protumor microenvironment. Notably, recent studies indicate that EVs have the potential to serve as a next-generation drug delivery platform for cancer treatment.

We invite authors to contribute original research articles, as well as review articles, of both in vitro and in vivo studies using animal and human models to this Special Issue on the mechanisms of cell–cell communication and EV-mediated tumorigenesis, metastasis, and antitumor treatment.

Dr. Kebin Hu
Dr. Yandong Zhou
Dr. Ling Lin
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. 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.

Published Papers (8 papers)

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Editorial

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3 pages, 170 KiB  
Editorial
Cell–Cell Communication and Extracellular Vesicles in Cancer
by Ling Lin, Yandong Zhou and Kebin Hu
Cancers 2023, 15(9), 2419; https://doi.org/10.3390/cancers15092419 - 23 Apr 2023
Cited by 2 | Viewed by 956
Abstract
Cell–cell communication, either through direct contact or indirectly, is critical for multiple cellular processes, such as proliferation, survival, differentiation, and transdifferentiation, and it plays a fundamental role in maintaining the integrity of tissue structure and cellular environment [...] Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)

Research

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17 pages, 3495 KiB  
Article
miR-214-Enriched Extracellular Vesicles Released by Acid-Adapted Melanoma Cells Promote Inflammatory Macrophage-Dependent Tumor Trans-Endothelial Migration
by Elena Andreucci, Jessica Ruzzolini, Francesca Bianchini, Giampaolo Versienti, Alessio Biagioni, Matteo Lulli, Daniele Guasti, Patrizia Nardini, Simona Serratì, Francesca Margheri, Anna Laurenzana, Chiara Nediani, Silvia Peppicelli and Lido Calorini
Cancers 2022, 14(20), 5090; https://doi.org/10.3390/cancers14205090 - 18 Oct 2022
Cited by 8 | Viewed by 1472
Abstract
The understanding of the molecular mechanisms leading to melanoma dissemination is urgently needed in view of the identification of new targets and the development of innovative strategies to improve patients’ outcomes. Within the complexity of tumor intercellular communications leading to metastatic dissemination, extracellular [...] Read more.
The understanding of the molecular mechanisms leading to melanoma dissemination is urgently needed in view of the identification of new targets and the development of innovative strategies to improve patients’ outcomes. Within the complexity of tumor intercellular communications leading to metastatic dissemination, extracellular vesicles (EV) released by tumor cells are central players. Indeed, the ability to travel through the circulatory system conveying oncogenic bioactive molecules even at distant sites makes EV capable of modulating recipient cells to facilitate metastatic dissemination. The dynamic remodeling of the tumor microenvironment might influence, along with a number of other events, tumoral EV release. We observed that, in melanoma, extracellular acidosis increases the release of EV enriched in miR-214, an onco-miRNA involved in melanoma metastasis. Then, miR-214-enriched EV were found to induce a state of macrophage activation, leading to an overproduction of proinflammatory cytokines and nitric oxide. Such an inflammatory microenvironment was able to alter the endothelial cell permeability, thereby facilitating the trans-endothelial migration of melanoma cells, a crucial step in the metastatic cascade. The use of synthetic miR-214 inhibitors and miR-214 overexpression allowed us to demonstrate the key role of miR-214 in the EV-dependent induction of macrophage activation. Overall, our in vitro study reveals that the release of tumor miR-214-enriched EV, potentiated by adapting tumor cells to extracellular acidosis, drives a macrophage-dependent trans-endothelial migration of melanoma cells. This finding points to miR-214 as a potential new therapeutic target to prevent melanoma intravasation. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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18 pages, 3800 KiB  
Article
A Novel Localization in Human Large Extracellular Vesicles for the EGF-CFC Founder Member CRIPTO and Its Biological and Therapeutic Implications
by Francesca Mantile, Matic Kisovec, Giorgia Adamo, Daniele P. Romancino, Matej Hočevar, Darja Božič, Apolonija Bedina Zavec, Marjetka Podobnik, Maria Patrizia Stoppelli, Annamaria Kisslinger, Antonella Bongiovanni, Veronika Kralj-Iglič and Giovanna L. Liguori
Cancers 2022, 14(15), 3700; https://doi.org/10.3390/cancers14153700 - 29 Jul 2022
Cited by 7 | Viewed by 1582
Abstract
Tumor growth and metastasis strongly rely on cell–cell communication. One of the mechanisms by which tumor cells communicate involves the release and uptake of lipid membrane encapsulated particles full of bioactive molecules, called extracellular vesicles (EVs). EV exchange between cancer cells may induce [...] Read more.
Tumor growth and metastasis strongly rely on cell–cell communication. One of the mechanisms by which tumor cells communicate involves the release and uptake of lipid membrane encapsulated particles full of bioactive molecules, called extracellular vesicles (EVs). EV exchange between cancer cells may induce phenotype changes in the recipient cells. Our work investigated the effect of EVs released by teratocarcinoma cells on glioblastoma (GBM) cells. EVs were isolated by differential centrifugation and analyzed through Western blot, nanoparticle tracking analysis, and electron microscopy. The effect of large EVs on GBM cells was tested through cell migration, proliferation, and drug-sensitivity assays, and resulted in a specific impairment in cell migration with no effects on proliferation and drug-sensitivity. Noticeably, we found the presence of the EGF-CFC founder member CRIPTO on both small and large EVs, in the latter case implicated in the EV-mediated negative regulation of GBM cell migration. Our data let us propose a novel route and function for CRIPTO during tumorigenesis, highlighting a complex scenario regulating its effect, and paving the way to novel strategies to control cell migration, to ultimately improve the prognosis and quality of life of GBM patients. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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15 pages, 3152 KiB  
Article
Prostate-Specific Membrane Antigen (PSMA)-Positive Extracellular Vesicles in Urine—A Potential Liquid Biopsy Strategy for Prostate Cancer Diagnosis?
by Susann Allelein, Keshia Aerchlimann, Gundula Rösch, Roxana Khajehamiri, Andreas Kölsch, Christian Freese and Dirk Kuhlmeier
Cancers 2022, 14(12), 2987; https://doi.org/10.3390/cancers14122987 - 17 Jun 2022
Cited by 7 | Viewed by 2585
Abstract
All cells release extracellular vesicles (EVs) to communicate with adjacent and distant cells. Consequently, circulating EVs are found in all bodily fluids, providing information applicable for liquid biopsy in early cancer diagnosis. Studies observed an overexpression of the membrane-bound prostate-specific membrane antigen (PSMA) [...] Read more.
All cells release extracellular vesicles (EVs) to communicate with adjacent and distant cells. Consequently, circulating EVs are found in all bodily fluids, providing information applicable for liquid biopsy in early cancer diagnosis. Studies observed an overexpression of the membrane-bound prostate-specific membrane antigen (PSMA) on prostate cancer cells. To investigate whether EVs derived from communicating prostate cells allow for reliable conclusions on prostate cancer development, we isolated PSMA-positive, as well as CD9-positive, EVs from cell-free urine with the use of magnetic beads. These populations of EVs were subsequently compared to CD9-positive EVs isolated from female urine in Western blotting, indicating the successful isolation of prostate-derived and ubiquitous EVs, respectively. Furthermore, we developed a device with an adapted protocol that enables an automated immunomagnetic enrichment of EVs of large sample volumes (up to 10 mL), while simultaneously reducing the overall bead loss and hands-on time. With an in-house spotted antibody microarray, we characterized PSMA as well as other EV surface markers of a prostate cohort of 44 urine samples in a more simplified way. In conclusion, the automated and specific enrichment of EVs from urine has a high potential for future diagnostic applications. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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29 pages, 2883 KiB  
Article
Exploration of Extracellular Vesicle miRNAs, Targeted mRNAs and Pathways in Prostate Cancer: Relation to Disease Status and Progression
by Maija Puhka, Lisse Thierens, Daniel Nicorici, Tarja Forsman, Tuomas Mirtti, Taija af Hällström, Elina Serkkola and Antti Rannikko
Cancers 2022, 14(3), 532; https://doi.org/10.3390/cancers14030532 - 21 Jan 2022
Cited by 7 | Viewed by 3454
Abstract
Background: Prostate cancer (PCa) lacks non-invasive specific biomarkers for aggressive disease. We studied the potential of urinary extracellular vesicles (uEV) as a liquid PCa biopsy by focusing on the micro RNA (miRNA) cargo, target messenger RNA (mRNA) and pathway analysis. Methods: We subjected [...] Read more.
Background: Prostate cancer (PCa) lacks non-invasive specific biomarkers for aggressive disease. We studied the potential of urinary extracellular vesicles (uEV) as a liquid PCa biopsy by focusing on the micro RNA (miRNA) cargo, target messenger RNA (mRNA) and pathway analysis. Methods: We subjected uEV samples from 31 PCa patients (pre-prostatectomy) to miRNA sequencing and matched uEV and plasma EV (pEV) from three PCa patients to mRNA sequencing. EV quality control was performed by electron microscopy, Western blotting and particle and RNA analysis. We compared miRNA expression based on PCa status (Gleason Score) and progression (post-prostatectomy follow-up) and confirmed selected miRNAs by quantitative PCR. Expression of target mRNAs was mapped in matched EV. Results: Quality control showed typical small uEV, pEV, RNA and EV-protein marker enriched samples. Comparisons between PCa groups revealed mostly unique differentially expressed miRNAs. However, they targeted comprehensive and largely overlapping sets of cancer and progression-associated signalling, resistance, hormonal and immune pathways. Quantitative PCR confirmed changes in miR-892a (Gleason Score 7 vs. ≥8), miR-223-3p (progression vs. no progression) and miR-146a-5p (both comparisons). Their target mRNAs were expressed widely in PCa EV. Conclusions: PCa status and progression-linked RNAs in uEV are worth exploration in large personalized medicine trials. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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Review

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16 pages, 1202 KiB  
Review
Extracellular Vesicles in the Progression and Therapeutic Resistance of Nasopharyngeal Carcinoma
by Yunhan Shan, Peijun Zhou, Qin Zhou and Lifang Yang
Cancers 2022, 14(9), 2289; https://doi.org/10.3390/cancers14092289 - 04 May 2022
Cited by 8 | Viewed by 2083
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy largely associated with Epstein–Barr virus (EBV) infection, which is frequently reported in east and southeast Asia. Extracellular vesicles (EVs) originate from the endosome or plasma membrane, which plays a critical role in tumor pathogenesis for their [...] Read more.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy largely associated with Epstein–Barr virus (EBV) infection, which is frequently reported in east and southeast Asia. Extracellular vesicles (EVs) originate from the endosome or plasma membrane, which plays a critical role in tumor pathogenesis for their character of cell-cell communication and its cargos, including proteins, RNA, and other molecules that can target recipient cells and affect their progression. To date, numerous studies have indicated that EVs have crucial significance in the progression, metastasis, and therapeutic resistance of NPC. In this review, we not only summarize the interaction of NPC cells and the tumor microenvironment (TME) through EVs, but also explain the role of EVs in radiation and drug resistance of NPC, which poses a severe threat to cancer therapy. Therefore, EVs may show great potential as biomarkers in the early diagnosis of interfered targets of NPC therapy. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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15 pages, 1257 KiB  
Review
Energy Sources for Exosome Communication in a Cancer Microenvironment
by Abhimanyu Thakur, Amanda Johnson, Emily Jacobs, Kui Zhang, Jonathan Chen, Zhubo Wei, Qizhou Lian and Huanhuan Joyce Chen
Cancers 2022, 14(7), 1698; https://doi.org/10.3390/cancers14071698 - 27 Mar 2022
Cited by 29 | Viewed by 3728
Abstract
Exosomes are crucial extracellular vesicles (EVs) with a diameter of approximately 30–200 nm. They are released by most cell types in their extracellular milieu and carry various biomolecules, including proteins and nucleic acids. Exosomes are increasingly studied in various diseases, including cancer, due [...] Read more.
Exosomes are crucial extracellular vesicles (EVs) with a diameter of approximately 30–200 nm. They are released by most cell types in their extracellular milieu and carry various biomolecules, including proteins and nucleic acids. Exosomes are increasingly studied in various diseases, including cancer, due to their role in local and distant cell–cell communication in which they can promote tumor growth, cancer progression, and metastasis. Interestingly, a tremendous number of exosomes is released by malignant cancer cells, and these are then taken up by autologous and heterologous recipient stromal cells such as immune cells, cancer stem cells, and endothelial cells. All these events demand an enormous amount of energy and require that exosomes remain stable while having the capacity to reach distant sites and cross physical barriers. Nevertheless, there is a dearth of research pertaining to the energy sources of exosomes, and questions remain about how they maintain their motility in the tumor microenvironment (TME) and beyond. Moreover, exosomes can produce adenosine triphosphate (ATP), an important energy molecule required by all cells, and mitochondria have been identified as one of the exosomal cargoes. These findings strengthen the prospect of exosomal communication via transfer of mitochondria and the bioenergetics of target recipient cells. In the TME, the accumulation of ATP and lactate may facilitate the entry of exosomes into cancer cells to promote metastasis, as well as help to target cancer cells at the tumor site. This review highlights how exosomes obtain sufficient energy to thrive in the TME and communicate with distant physiological destinations. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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18 pages, 905 KiB  
Review
Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer
by Jialun Wang, Yu Chen, Xihan Li and Xiaoping Zou
Cancers 2021, 13(18), 4594; https://doi.org/10.3390/cancers13184594 - 13 Sep 2021
Cited by 22 | Viewed by 3760
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor–neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years. Full article
(This article belongs to the Special Issue Cell-Cell Communication and Extracellular Vesicles in Cancer)
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