Editorial

4 pages, 188 KiB

Open AccessEditorial

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 972

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

Open AccessFeature PaperArticle

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 11 | Viewed by 2390

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

Open AccessArticle

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 24 | Viewed by 2791

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

Open AccessArticle

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 - 08 Jul 2021

Cited by 16 | Viewed by 2381

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

Open AccessArticle

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 - 06 Jul 2021

Cited by 31 | Viewed by 3398

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

Open AccessArticle

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 14 | Viewed by 2893

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

Open AccessArticle

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 2725

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

Open AccessArticle

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 3041

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

Open AccessReview

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 22 | Viewed by 3144

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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