Translational Research on Exosomes in Cancer

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 26479

Special Issue Editors


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Guest Editor
Division of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
Interests: applied and experimental oncology; fibroblast growth factor receptor signaling; telomere maintenance mechanisms; alternative splicing; human and canine tumor cell models; novel therapeutic strategies; biomarkers
Special Issues, Collections and Topics in MDPI journals
Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale Cancer Center, Yale University, New Haven, CT, USA
Interests: immune checkpoints and cancer progression; immune escaping; immune responses; neoantigen presentation; T cell infiltration; microenvironmental factors; immune checkpoints; T cell activation; tumor progression; individualize immunotherapy

Special Issue Information

Dear Colleagues,

Exosomes are actively secreted from living cells and found in body fluids as membrane-structured nanovesicles which contain bioactive molecules such as proteins, RNAs, and lipids. The content reflects the donor cells with their microenvironment and plays key endocrine and paracrine roles in the cell–cell communication of diverse biological processes important for both benign and cancer cells.

Circulating tumor-associated exosomes are still not completely understood but have potential as non-invasive novel biomarkers of (human) cancer, with critical roles already shown in contributing to tumorigenesis, metastasis, and chemotherapy resistance. Exosomes are detectable in body fluids such as blood, salvia, and urine, making them attractive as biomarkers for early cancer detection, diagnosis, and prognosis, and as therapeutic targets and drug delivery vehicles for cancer therapy.

This Special Issue is calling for reviews and original papers covering translational research on exosomes in cancer from basic science to clinical studies with a strong emphasis on improving the knowledge for clinical application.

Dr. Klaus Holzmann
Dr. Lingeng Lu
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 (9 papers)

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Editorial

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4 pages, 188 KiB  
Editorial
Emerging Roles of Exosomes in Cancer for Possible Clinical Use
by Hedwig Sutterlüty and Klaus Holzmann
Cancers 2022, 14(19), 4603; https://doi.org/10.3390/cancers14194603 - 22 Sep 2022
Viewed by 1043
Abstract
Exosomes are membrane-structured extracellular vesicles (EVs) with nano-scale size that are released from different cell types [...] Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)

Research

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17 pages, 15648 KiB  
Article
Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy
by Hae Hyun Jung, Ji-Yeon Kim, Eun Yoon Cho, Jung Min Oh, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Yeon Hee Park, Jin Seok Ahn and Young-Hyuck Im
Cancers 2021, 13(21), 5260; https://doi.org/10.3390/cancers13215260 - 20 Oct 2021
Cited by 13 | Viewed by 2512
Abstract
Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players [...] Read more.
Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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18 pages, 4016 KiB  
Article
Esophageal Cancer-Derived Extracellular Vesicle miR-21-5p Contributes to EMT of ESCC Cells by Disorganizing Macrophage Polarization
by Jing Song, Peiyan Yang, Xiuwen Li, Xinyi Zhu, Mengxin Liu, Xuexin Duan and Ran Liu
Cancers 2021, 13(16), 4122; https://doi.org/10.3390/cancers13164122 - 16 Aug 2021
Cited by 26 | Viewed by 2930
Abstract
The disorganized polarization of tumor-associated macrophages (TAMs) exerts a critical effect on tumor progression. MicroRNAs (miRNAs) in extracellular vesicles (EVs) secreted from cancer cells may contribute to this process. However, the relationship between TAMs and EVs-miRNAs-mediated regulation in esophageal squamous cell carcinoma (ESCC) [...] Read more.
The disorganized polarization of tumor-associated macrophages (TAMs) exerts a critical effect on tumor progression. MicroRNAs (miRNAs) in extracellular vesicles (EVs) secreted from cancer cells may contribute to this process. However, the relationship between TAMs and EVs-miRNAs-mediated regulation in esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, immunoaffinity magnetic beads combined with antiepithelial cell adhesion molecules (EpCAM) were used to isolate and identify EVs-miR-21-5p from the plasma of ESCC patients. An in vitro coculture system was designed to evaluate the effect of esophageal cancer cells with miR-21-5p overexpression on macrophage polarization. We found that phorbol myristate acetate-induced THP-1 macrophages took up EVs-miR-21-5p from EC109 or EC9706 cells and were transformed into M2 macrophages. This, in turn, contributed to the excessive migration and invasion of esophageal cancer cells. The mechanism underlying these changes may involve activation of M2 macrophages by upregulated ESCC-derived EVs-miR-21-5p through the PTEN/AKT/STAT6 pathway. This may result in esophageal cancer cell epithelial-mesenchymal transition (EMT) via TGF-β/Smad2 signaling. Our results indicate positive feedback between M2 macrophage polarization and EMT of esophageal cancer cells in the tumor microenvironment via shuttling of miR-21-5p in tumor-derived EVs. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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14 pages, 2138 KiB  
Article
The Lipid Composition of Serum-Derived Small Extracellular Vesicles in Participants of a Lung Cancer Screening Study
by Mateusz Smolarz, Agata Kurczyk, Karol Jelonek, Joanna Żyła, Łukasz Mielańczyk, Magdalena Sitkiewicz, Monika Pietrowska, Joanna Polańska, Witold Rzyman and Piotr Widłak
Cancers 2021, 13(14), 3414; https://doi.org/10.3390/cancers13143414 - 8 Jul 2021
Cited by 17 | Viewed by 2498
Abstract
Molecular components of exosomes and other classes of small extracellular vesicles (sEV) present in human biofluids are potential biomarkers with possible applicability in the early detection of lung cancer. Here, we compared the lipid profiles of serum-derived sEV from three groups of lung [...] Read more.
Molecular components of exosomes and other classes of small extracellular vesicles (sEV) present in human biofluids are potential biomarkers with possible applicability in the early detection of lung cancer. Here, we compared the lipid profiles of serum-derived sEV from three groups of lung cancer screening participants: individuals without pulmonary alterations, individuals with benign lung nodules, and patients with screening-detected lung cancer (81 individuals in each group). Extracellular vesicles and particles were purified from serum by size-exclusion chromatography, and a fraction enriched in sEV and depleted of low-density lipoproteins (LDLs) was selected (similar sized vesicles was observed in all groups: 70–100 nm). The targeted mass-spectrometry-based approach enabled the detection of 352 lipids, including 201 compounds used in quantitative analyses. A few compounds, exemplified by Cer(42:1), i.e., a ceramide whose increased plasma/serum level was reported in different pathological conditions, were upregulated in vesicles from cancer patients. On the other hand, the contribution of phosphatidylcholines with poly-unsaturated acyl chains was reduced in vesicles from lung cancer patients. Cancer-related features detected in serum-derived sEV were different than those of the corresponding whole serum. A high heterogeneity of lipid profiles of sEV was observed, which markedly impaired the performance of classification models based on specific compounds (the three-state classifiers showed an average AUC = 0.65 and 0.58 in the training and test subsets, respectively). Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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26 pages, 7849 KiB  
Article
Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence
by Mona Alharbi, Andrew Lai, Shayna Sharma, Priyakshi Kalita-de Croft, Nihar Godbole, America Campos, Dominic Guanzon, Alexis Salas-Burgos, Flavio Carrion, Felipe A. Zuñiga, Lewis Perrin, Yaowu He, Tanja Pejovic, Carmen Winters, Terry Morgan, John D. Hooper, Gregory E. Rice and Carlos Salomon
Cancers 2021, 13(14), 3388; https://doi.org/10.3390/cancers13143388 - 6 Jul 2021
Cited by 33 | Viewed by 3536
Abstract
Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a [...] Read more.
Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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15 pages, 3484 KiB  
Article
A Circulating Exosome RNA Signature Is a Potential Diagnostic Marker for Pancreatic Cancer, a Systematic Study
by Yixing Wu, Hongmei Zeng, Qing Yu, Huatian Huang, Beatrice Fervers, Zhe-Sheng Chen and Lingeng Lu
Cancers 2021, 13(11), 2565; https://doi.org/10.3390/cancers13112565 - 24 May 2021
Cited by 15 | Viewed by 3018
Abstract
Several exosome proteins, miRNAs and KRAS mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in [...] Read more.
Several exosome proteins, miRNAs and KRAS mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in the diagnosis of pancreatic cancer. The purpose of this study was to investigate the potential of circulating exosome RNAs in pancreatic cancer detection. By retrieving RNA-seq data from publicly accessed databases, differential expression and random-effects meta-analyses were performed. The results showed that pancreatic cancer had a distinct circulating exosome RNA signature in healthy individuals, and that the top 10 candidate exosome RNAs could distinguish patients from healthy individuals with an area under the curve (AUC) of 1.0. Three (HIST2H2AA3, LUZP6 and HLA-DRA) of the 10 genes in exosomes had similar differential patterns to those in tumor tissues based on RNA-seq data. In the validation dataset, the levels of these three genes in exosomes displayed good performance in distinguishing cancer from both chronic pancreatitis (AUC = 0.815) and healthy controls (AUC = 0.8558), whereas a slight difference existed between chronic pancreatitis and healthy controls (AUC = 0.586). Of the three genes, the level of HIST2H2AA3 was positively associated with KRAS status. However, there was no significant difference in the levels of the three genes across the disease stages (stages I–IV). These findings indicate that circulating exosome RNAs have a potential early detection value in pancreatic cancer, and that a distinct exosome RNA signature exists in distinguishing pancreatic cancer from healthy individuals. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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20 pages, 17696 KiB  
Article
Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma
by Suguru Yokoo, Tomohiro Fujiwara, Aki Yoshida, Koji Uotani, Takuya Morita, Masahiro Kiyono, Joe Hasei, Eiji Nakata, Toshiyuki Kunisada, Shintaro Iwata, Tsukasa Yonemoto, Koji Ueda and Toshifumi Ozaki
Cancers 2021, 13(8), 1823; https://doi.org/10.3390/cancers13081823 - 11 Apr 2021
Cited by 7 | Viewed by 2802
Abstract
The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic [...] Read more.
The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1+CD9+ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1+CD9+ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1+CD9+ EVs and indicates the therapeutic potential of MCT1 in SS. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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20 pages, 2551 KiB  
Article
Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells
by Jakub Godlewski, Mohamed Farhath, Franz L. Ricklefs, Carmela Passaro, Klaudia Kiel, Hiroshi Nakashima, E. Antonio Chiocca and Agnieszka Bronisz
Cancers 2021, 13(6), 1287; https://doi.org/10.3390/cancers13061287 - 14 Mar 2021
Cited by 8 | Viewed by 3158
Abstract
Oncolytic virus (OV) therapy, which is being tested in clinical trials for glioblastoma, targets cancer cells, while triggering immune cells. Yet OV sensitivity varies from patient to patient. As OV therapy is regarded as an anti-tumor vaccine, by making OV-infected cancer cells secrete [...] Read more.
Oncolytic virus (OV) therapy, which is being tested in clinical trials for glioblastoma, targets cancer cells, while triggering immune cells. Yet OV sensitivity varies from patient to patient. As OV therapy is regarded as an anti-tumor vaccine, by making OV-infected cancer cells secrete immunogenic proteins, linking these proteins to transcriptome would provide a measuring tool to predict their sensitivity. A set of six patient-derived glioblastoma cells treated ex-vivo with herpes simplex virus type 1 (HSV1) modeled a clinical setting of OV infection. The cellular transcriptome and secreted proteome (separated into extracellular vesicles (EV) and EV-depleted fractions) were analyzed by gene microarray and mass-spectroscopy, respectively. Data validation and in silico analysis measured and correlated the secretome content with the response to infection and patient survival. Glioblastoma cells reacted to the OV infection in a seemingly dissimilar fashion, but their transcriptomes changed in the same direction. Therefore, the upregulation of transcripts encoding for secreted proteins implies a common thread in the response of cancer cells to infection. Indeed, the OV-driven secretome is linked to the immune response. While these proteins have distinct membership in either EV or EV-depleted fractions, it is their co-secretion that augments the immune response and associates with favorable patient outcomes. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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Review

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22 pages, 1997 KiB  
Review
Characteristics and Clinical Application of Extracellular Vesicle-Derived DNA
by Jae Young Hur and Kye Young Lee
Cancers 2021, 13(15), 3827; https://doi.org/10.3390/cancers13153827 - 29 Jul 2021
Cited by 23 | Viewed by 3317
Abstract
Extracellular vesicles (EVs) carry RNA, proteins, lipids, and diverse biomolecules for intercellular communication. Recent studies have reported that EVs contain double-stranded DNA (dsDNA) and oncogenic mutant DNA. The advantage of EV-derived DNA (EV DNA) over cell-free DNA (cfDNA) is the stability achieved through [...] Read more.
Extracellular vesicles (EVs) carry RNA, proteins, lipids, and diverse biomolecules for intercellular communication. Recent studies have reported that EVs contain double-stranded DNA (dsDNA) and oncogenic mutant DNA. The advantage of EV-derived DNA (EV DNA) over cell-free DNA (cfDNA) is the stability achieved through the encapsulation in the lipid bilayer of EVs, which protects EV DNA from degradation by external factors. The existence of DNA and its stability make EVs a useful source of biomarkers. However, fundamental research on EV DNA remains limited, and many aspects of EV DNA are poorly understood. This review examines the known characteristics of EV DNA, biogenesis of DNA-containing EVs, methylation, and next-generation sequencing (NGS) analysis using EV DNA for biomarker detection. On the basis of this knowledge, this review explores how EV DNA can be incorporated into diagnosis and prognosis in clinical settings, as well as gene transfer of EV DNA and its therapeutic potential. Full article
(This article belongs to the Special Issue Translational Research on Exosomes in Cancer)
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