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Zemanek T, Danisovic L, Nicodemou A. Exosomes and solid cancer therapy: where are we now? Med Oncol 2025; 42:77. [PMID: 39961904 PMCID: PMC11832697 DOI: 10.1007/s12032-025-02626-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Cancer immunotherapy has revolutionized oncology, offering new hope for patients with previously incurable cancers. However, solid tumors remain a significant challenge due to immune evasion, therapeutic resistance, and the immunosuppressive tumor microenvironment. Exosomes, a specialized subset of extracellular vesicles, have emerged as promising tools in cancer therapy owing to their unique role in intercellular communication and immune modulation. These vesicles transport antigens, major histocompatibility complex (MHC) molecules, and immune-modulatory cargo, positioning them as potential platforms for cancer vaccines, drug delivery systems, and combinatorial therapies. Advances in engineered exosomes have improved drug bioavailability, tumor targeting, and immune stimulation, showcasing their potential in personalized medicine. This review highlights their multifaceted role in the tumor microenvironment, and their mechanisms of action in solid cancer therapy. Additionally, we discuss emerging strategies to overcome clinical and technical hurdles, paving the way for novel and effective cancer treatments.
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Affiliation(s)
- Tomas Zemanek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
- GAMMA - ZA s.r.o., Trencin, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Andreas Nicodemou
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
- GAMMA - ZA s.r.o., Trencin, Slovakia.
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Wu Y, Xiao Y, Ding Y, Ran R, Wei K, Tao S, Mao H, Wang J, Pang S, Shi J, Zhu C, Wan W, Yang Q, Chen C. Colorectal cancer cell-derived exosomal miRNA-372-5p induces immune escape from colorectal cancer via PTEN/AKT/NF-κB/PD-L1 pathway. Int Immunopharmacol 2024; 143:113261. [PMID: 39353381 DOI: 10.1016/j.intimp.2024.113261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Tumor cells can escape immune surveillance by changing their own escape or expressing abnormal genes and proteins, resulting in unlimited proliferation and invasive growth of cells. These changes are related to microRNAs (miRNAs), which reduce the killing effect of immune cells, devastate the immune response, and interfere with apoptosis through the aberrant expression of relevant miRNAs. In the preliminary phase of this study, miRNAs in clinical plasma exosomes of colorectal cancer patients were differentially analyzed by RNA sequencing technology, and miR-372-5p derived from extracellular vesicles (sEVs) was found to be a key signaling molecule mediating the regulation of macrophages by colorectal cancer (CRC). miRNA-372-5p is upregulated in colorectal cancer patient tissues and serum, as well as colorectal cancer cell lines and their exosomes. Subsequently, we found that macrophages could take up sEV secreted by colorectal cancer cells HCT116, affecting the expression of the immune checkpoint PD-L1, resulting in the generation of a tumor-immunosuppressive microenvironment and suppression of T cell activation in CRC. Gene enrichment mapping and database revealed that miR-372-5p regulates PD-L1 expression in colorectal cancer through the homologous phosphatase-tensin (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT)-nuclear factor-κB (NF-κB) pathway. Further studies confirmed that miRNA-372-5p-treated macrophages co-cultured with T cells affected the regulation of PD-L1 expression through the PTEN/AKT/NF-κB signaling pathway, resulting in decreased CD3+CD8+ T cell activity, decreased cytokine IL-2 and increased IFN-γ. And miRNA-372-5p could down-regulate the expression of PD-L1 in HCT116 through the PTEN/AKT/NF-κB pathway, inhibit tumor cell proliferation and promote apoptosis. Conclusion: Colorectal cancer cell-derived exosome miR-372-5p can be phagocytosed by colorectal cancer and macrophage cells, regulate the expression of PD-L1 in colorectal cancer cells and macrophages by targeting the PTEN/AKT/NF-κB pathway, and induce the immunosuppressive microenvironment of CRC to promote CRC development. This suggests that inhibiting the secretion of HCT116-specific sEV-miR-372-5p or targeting PD-L1 in tumor-associated macrophages could be a novel approach for CRC treatment and possibly a sensitizing approach for CRC anti-PD-L1 therapy.
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Affiliation(s)
- Yulun Wu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China.
| | - Yuhan Xiao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; School of Laboratory Medicine, Bengbu Medical University, Anhui 233030, China.
| | - Yongxing Ding
- The Third the Pople's Hospital of Bengbu, Anhui 233000, China.
| | - Ruorong Ran
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Ke Wei
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Shuang Tao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Huilan Mao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jing Wang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Siyan Pang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jiwen Shi
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Chengle Zhu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Wenrui Wan
- Department of Biotechnology, Bengbu Medical University, Anhui 233030, China.
| | - Qingling Yang
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
| | - Changjie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
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Yang Y, Wu T, Wang Y, Luo D, Zhao Z, Sun H, Zhang M, Zhang B, Han B. Hypoxic tumour-derived exosomal miR-1290 exacerbates the suppression of CD8+ T cells by promoting M2 macrophage polarization. Immunology 2024; 173:672-688. [PMID: 39183579 DOI: 10.1111/imm.13853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 07/30/2024] [Indexed: 08/27/2024] Open
Abstract
Hypoxia plays an important role in the metastasis of hepatocellular carcinoma (HCC). Exosomes have been widely studied as mediators of communication between tumours and immune cells. However, the specific mechanism by which hypoxic HCC cell-derived exosomes suppress antitumor immunity is unclear. Hypoxia scores were determined for The Cancer Genome-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset patients, and HCC patients in the hyperhypoxic group had a higher degree of M2 macrophage infiltration. Patients in the M2 high-invasion group had a lower probability of survival than those in the low-invasion group. In vivo and in vitro experiments demonstrated that exosomes secreted by hypoxic HCC cells promote M2 macrophage polarization. This polarization induces apoptosis in CD8+ T cells. Additionally, it encourages epithelial-mesenchymal transition (EMT), which increases HCC migration. Exosomal miRNA sequencing revealed that miR-1290 was highly expressed in exosomes secreted by hypoxic HCC cells. Mechanistically, miR-1290 in macrophages inhibited Akt2 while upregulating PD-L1 to promote M2 polarization, induce apoptosis in CD8+ T cells, and enhance EMT in HCC. Animal studies found that the miR-1290 antagomir in combination with the immune checkpoint inhibitor produced better antitumor effects than the monotherapies. In conclusion, the secretion of exosome-derived miR-1290 from HCC cells in a hypoxic environment supported immune escape by HCC cells by promoting M2 macrophage polarization to induce apoptosis in CD8+ T cells and enhance EMT that promoted HCC metastasis. Therefore, miR-1290 is an important molecule in antitumor immunity in HCC, and inhibition of miR-1290 could provide a novel immunotherapeutic approach for HCC treatment.
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Affiliation(s)
- Yeni Yang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tiansong Wu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Youpeng Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dingan Luo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ziyin Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongfa Sun
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mao Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin Zhang
- Department of Transplantation, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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Li L, Yang Z, Li J. Exosomes and SARS-CoV-2 infection. Front Immunol 2024; 15:1467109. [PMID: 39660145 PMCID: PMC11628517 DOI: 10.3389/fimmu.2024.1467109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Exosomes, which are small extracellular vesicles, are of particular interest in studies on SARS-CoV-2 infection because of their crucial role in intercellular communication. These vesicles are released by several cell types and are rich in "cargo" such as proteins, lipids, and nucleic acids, which are vital for regulating immune response and viral pathogenesis. Exosomes have been reported to be involved in viral transmission, immune escape mechanisms, and illness development in SARS-CoV-2 infection. This review examines the current research on the contribution of exosomes to the interplay between the virus and host cells, highlighting their potential as diagnostic biomarkers and therapeutic targets in combating COVID-19.
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Affiliation(s)
- Liuying Li
- Department of Traditional Chinese Medicine, Zigong First People’s Hospital, Zigong, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zixuan Yang
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Li
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Bugajova M, Raudenska M, Masarik M, Kalfert D, Betka J, Balvan J. RNAs in tumour-derived extracellular vesicles and their significance in the tumour microenvironment. Int J Cancer 2024; 155:1147-1161. [PMID: 38845351 DOI: 10.1002/ijc.35035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/11/2024] [Accepted: 05/03/2024] [Indexed: 08/03/2024]
Abstract
Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.
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Affiliation(s)
- Maria Bugajova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Martina Raudenska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Michal Masarik
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Praha, Czech Republic
| | - David Kalfert
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jan Betka
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Zhang Y, Ding N, Cao J, Zhang J, Liu J, Zhang C, Jiang L. Proteomics and Metabolic Characteristics of Boar Seminal Plasma Extracellular Vesicles Reveal Biomarker Candidates Related to Sperm Motility. J Proteome Res 2024; 23:3764-3779. [PMID: 39067049 PMCID: PMC11385425 DOI: 10.1021/acs.jproteome.4c00060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Although seminal plasma extracellular vesicles (SPEVs) play important roles in sperm function, little is known about their metabolite compositions and roles in sperm motility. Here, we performed metabolomics and proteomics analysis of boar SPEVs with high or low sperm motility to investigate specific biomarkers affecting sperm motility. In total, 140 proteins and 32 metabolites were obtained through differentially expressed analysis and weighted gene coexpression network analysis (WGCNA). Seven differentially expressed proteins (DEPs) (ADIRF, EPS8L1, PRCP, CD81, PTPRD, CSK, LOC100736569) and six differentially expressed metabolites (DEMs) (adenosine, beclomethasone, 1,2-benzenedicarboxylic acid, urea, 1-methyl-l-histidine, and palmitic acid) were also identified in WGCNA significant modules. Joint pathway analysis revealed that three DEPs (GART, ADCY7, and NTPCR) and two DEMs (urea and adenosine) were involved in purine metabolism. Our results suggested that there was significant correlation between proteins and metabolites, such as IL4I1 and urea (r = 0.86). Furthermore, we detected the expression level of GART, ADCY7, and CDC42 in sperm of two groups, which further verified the experimental results. This study revealed that several proteins and metabolites in SPEVs play important roles in sperm motility. Our results offered new insights into the complex mechanism of sperm motility and identified potential biomarkers for male reproductive diseases.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Ning Ding
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Jinkang Cao
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Jing Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Jianfeng Liu
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Chun Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
| | - Li Jiang
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, P. R. China
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Yuan L, Ji H, Cao Y, Yi H, Leng Q, Zhou J, Mei X. Exosomes in esophageal cancer: Promising nanocarriers in cancer progression, diagnosis, prognosis, and therapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1989. [PMID: 39217461 DOI: 10.1002/wnan.1989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/26/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
Esophageal cancer (EC) is one of the most fatal cancers all over the world. Sensitive detection modalities for early-stage EC and efficient treatment methods are urgently needed for the improvement of the prognosis of EC. Exosomes are small vesicles for intercellular communication, mediating many biological responses including cancer progression, which are not only promising biomarkers for diagnosis and prognosis but also therapeutic tools for EC. This review provides an overview of the relationships between exosomes and EC progression, as well as the application of exosomes in the diagnosis, prognosis, and treatment of EC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Ligong Yuan
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haoran Ji
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yang Cao
- Peking University Health Science Center, Peking University, Beijing, China
| | - Hang Yi
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qihao Leng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jie Zhou
- Department of Chemistry and Biochemistry, University of California San Diego, San Diego, California, USA
| | - Xinyu Mei
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Liu Z, Huang H, Ren J, Song T, Ni Y, Mao S, Yang Y, Liu D, Tang H. Plasma exosomes contain protein biomarkers valuable for the diagnosis of lung cancer. Discov Oncol 2024; 15:194. [PMID: 38806979 PMCID: PMC11133266 DOI: 10.1007/s12672-024-01022-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 05/08/2024] [Indexed: 05/30/2024] Open
Abstract
Accumulating evidence indicates that exosomal proteins are critical in diagnosing malignant tumors. To identify novel exosomal biomarkers for lung cancer diagnosis, we isolated plasma exosomes from 517 lung cancer patients and 168 healthy controls (NLs)-186 lung adenocarcinoma (LUAD) patients (screening (SN): 20, validation (VD): 166), 159 lung squamous carcinoma (LUSC) patients (SN: 20, VD: 139), 172 benign nodules (LUBN) patients (SN: 20, VD: 152) and 168 NLs (SN: 20, VD: 148)-and randomly assigned them to the SN or VD group. Proteomic analysis by LC-MS/MS and PRM were performed on all groups. The candidate humoral markers were evaluated and screened by a machine learning method. All selected biomarkers were identified in the VD groups. For LUAD, a 7-protein panel had AUCs of 97.9% and 87.6% in the training and test sets, respectively, and 89.5% for early LUAD. For LUSC, an 8-protein panel showed AUCs of 99.1% and 87.0% in the training and test sets and 92.3% for early LUSC. For LUAD + LUSC (LC), an 8-protein panel showed AUCs of 85.9% and 80.3% in the training and test sets and 87.1% for early LC diagnosis. The characteristics of the exosomal proteome make exosomes potential diagnostic tools.
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Affiliation(s)
- Zhiqiang Liu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Hong Huang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Jing Ren
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Tingting Song
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Yinyun Ni
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Shengqiang Mao
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Ying Yang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China
| | - Dan Liu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
- Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China.
| | - Huairong Tang
- Center of Health Management, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
- The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, China.
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Wang C, He J, Chen C, Luo W, Dang X, Mao L. A potential role of human esophageal cancer-related gene-4 in cardiovascular homeostasis. Gene 2024; 894:147977. [PMID: 37956966 DOI: 10.1016/j.gene.2023.147977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/10/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
Human esophageal cancer related gene-4 (ECRG-4) encodes a 148-aminoacid pre-pro-peptide that can be processed tissue-dependently into multiple small peptides possessing multiple functions distinct from, similar to, or opposite to the tumor suppressor function of the full-length Ecrg4. Ecrg-4 is covalently bound to the cell surface through its signal peptide, colocalized with the innate immunity complex (TLR4-CD14-MD2), and functions as a 'sentinel' molecule in the maintenance of epithelium and leukocyte homeostasis, meaning that the presence of Ecrg-4 on the cell surface signals the maintained homeostasis, whereas the loss of Ecrg-4 due to tissue injury activates pro-inflammatory and tissue proliferative responses, and the level of Ecrg-4 gradually returns to its pre-injury level upon wound healing. Interestingly, Ecrg-4 is also highly expressed in the heart and its conduction system, endothelial cells, and vascular smooth muscle cells. Accumulating evidence has shown that Ecrg-4 is involved in cardiac rate/rhythm control, the development of atrial fibrillation, doxorubicin-induced cardiotoxicity, the ischemic response of the heart and hypoxic response in the carotid body, the pathogenesis of atherosclerosis, and likely the endemic incidence of idiopathic dilated cardiomyopathy. These preliminary discoveries suggest that Ecrg-4 may function as a 'sentinel' molecule in cardiovascular system as well. Here, we briefly review the basic characteristics of ECRG-4 as a tumor suppressor gene and its regulatory functions on inflammation and apoptosis; summarize the discoveries about its distribution in cardiovascular system and involvement in the development of CVDs, and discuss its potential as a novel therapeutic target for the maintenance of cardiovascular system homeostasis.
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Affiliation(s)
- Chaoying Wang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Jianghui He
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Chunyue Chen
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Wenjun Luo
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Xitong Dang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China.
| | - Liang Mao
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China; Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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10
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Lee SM, Cho J, Choi S, Kim DH, Ryu JW, Kim I, Woo DC, Sung YH, Jeong JY, Baek IJ, Pack CG, Rho JK, Lee SW, Ha CH. HDAC5-mediated exosomal Maspin and miR-151a-3p as biomarkers for enhancing radiation treatment sensitivity in hepatocellular carcinoma. Biomater Res 2023; 27:134. [PMID: 38102691 PMCID: PMC10725039 DOI: 10.1186/s40824-023-00467-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Tumor-derived exosomes are critical elements of the cell-cell communication response to various stimuli. This study aims to reveal that the histone deacetylase 5 (HDAC5) and p53 interaction upon radiation in hepatocellular carcinoma intricately regulates the secretion and composition of exosomes. METHODS We observed that HDAC5 and p53 expression were significantly increased by 2 Gy and 4 Gy radiation exposure in HCC. Normal- and radiation-derived exosomes released by HepG2 were purified to investigate the exosomal components. RESULTS We found that in the radiation-derived exosome, exosomal Maspin was notably increased. Maspin is known as an anti-angiogenic gene. The expression of Maspin was regulated at the cellular level by HDAC5, and it was elaborately regulated and released in the exosome. Radiation-derived exosome treatment caused significant inhibition of angiogenesis in HUVECs and mouse aortic tissues. Meanwhile, we confirmed that miR-151a-3p was significantly reduced in the radiation-derived exosome through exosomal miRNA sequencing, and three HCC-specific exosomal miRNAs were also decreased. In particular, miR-151a-3p induced an anti-apoptotic response by inhibiting p53, and it was shown to induce EMT and promote tumor growth by regulating p53-related tumor progression genes. In the HCC xenograft model, radiation-induced exosome injection significantly reduced angiogenesis and tumor size. CONCLUSIONS Our present findings demonstrated HDAC5 is a vital gene of the p53-mediated release of exosomes resulting in tumor suppression through anti-cancer exosomal components in response to radiation. Finally, we highlight the important role of exosomal Maspin and mi-151a-3p as a biomarker in enhancing radiation treatment sensitivity. Therapeutic potential of HDAC5 through p53-mediated exosome modulation in radiation treatment of hepatocellular carcinoma.
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Affiliation(s)
- Seung Min Lee
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Jeongin Cho
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Sujin Choi
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Dong Ha Kim
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Je-Won Ryu
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Inki Kim
- Department of Pharmacology, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Cheol Woo
- Department of Biomedical Engineering, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Hoon Sung
- Department of Cell and Genetic Engineering, Asan Medical Center, Asan Institute for Life Sciences University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin-Yong Jeong
- Department of Microbiology, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Jeoung Baek
- Department of Cell and Genetic Engineering, Asan Medical Center, Asan Institute for Life Sciences University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chan-Gi Pack
- Department of Biomedical Engineering, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin Kyung Rho
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Sang-Wook Lee
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
| | - Chang Hoon Ha
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
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11
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Wang Z, Ding J, Xiao Y, Xiao K, Su P, Dong Z, Zhang Y. Serum extracellular vesicles with NSD1 and FBXO7 mRNA as novel biomarkers for gastric cancer. Clin Biochem 2023; 120:110653. [PMID: 37742869 DOI: 10.1016/j.clinbiochem.2023.110653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Messenger RNAs (mRNAs) in serum extracellular vesicles (EVs) are effective non-invasive biomarkers for various types of cancer, however, their role as biomarkers for gastric cancer is yet to be investigated. Therefore, the current study was designed to explore their potential as novel biomarkers for gastric cancer. METHODS The mRNAs in serum EVs from four patients with gastric cancer and four healthy controls were investigated. mRNAs in serum EVs were extracted for high-throughput RNA sequencing (RNA-seq). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict cancer-related genes. Candidate mRNAs were validated using reverse transcription-quantitative polymerase chain reaction. The diagnostic and prognostic values of mRNAs for gastric cancer were evaluated by receiver operating characteristic (ROC) curves and Kaplan-Meier analysis, respectively. RESULTS RNA-seq revealed 13,229 upregulated and 7,079 downregulated mRNAs in serum EVs. GO and KEGG analyses showed that certain mRNAs were associated with tumorigenesis and progression. From these, 10 were selected according to our criteria (|Fold Change| > 10, P < 0.05). NSD1 was upregulated and FBXO7 was downregulated in patients with gastric cancer compared with the healthy controls. The area under the ROC curves of these two mRNAs combined was 0.84, with a sensitivity of 78 % and a specificity of 92 %. NSD1 and FBXO7 were also associated with tumor size, distal metastasis, and TNM stage. Furthermore, NSD1 expression was strongly associated with prognosis, as revealed from our follow-up studies and online database analysis. However, FBXO7 was only significantly associated with prognosis in our follow-up data. CONCLUSIONS NSD1 and FBXO7 in serum EVs have important roles in gastric cancer and may be useful biomarkers for its diagnosis and prognosis.
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Affiliation(s)
- Zhen Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Juan Ding
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Yilei Xiao
- Department of Neurosurgery, Liaocheng People's Hospital, 67 Dongchangxi Road, Liaocheng 252000, Shandong, China
| | - Ke Xiao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Ping Su
- National Administration of Health Data, Jinan 250000, Shandong, China
| | - Zhaogang Dong
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
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12
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Wu Q, Li L, Jia Y, Xu T, Zhou X. Advances in studies of circulating microRNAs: origination, transportation, and distal target regulation. J Cell Commun Signal 2023; 17:445-455. [PMID: 36357651 PMCID: PMC9648873 DOI: 10.1007/s12079-022-00705-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 10/07/2022] [Indexed: 11/12/2022] Open
Abstract
In the past few years, numerous advances emerged in terms of circulating microRNA(miRNA) regulating gene expression by circulating blood to the distal tissues and cells. This article reviewed and summarized the process of circulating miRNAs entering the circulating system to exert gene regulation, especially exogenous miRNAs (such as plant miRNAs), from the perspective of the circulating miRNAs source (cell secretion or gastrointestinal absorption), the transport form and pharmacokinetics in circulating blood, and the evidence of distal regulation to gene expression, thereby providing a basis for their in-depth research and even application prospects.
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Affiliation(s)
- Qingni Wu
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
| | - Longxue Li
- Laboratory Animal Science and Technology Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
- Key Laboratory of Animal Model of TCM Syndromes of Depression, Jiangxi Administration of traditional Chinese Medicine, 330004, Nanchang, China
| | - Yao Jia
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
| | - Tielong Xu
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China.
| | - Xu Zhou
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China.
- Key Laboratory of Drug-Targeting and Drug Delivery System of Sichuan Province, 610000, Chengdu, China.
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13
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Liu K, Dou R, Yang C, Di Z, Shi D, Zhang C, Song J, Fang Y, Huang S, Xiang Z, Zhang W, Wang S, Xiong B. Exosome-transmitted miR-29a induces colorectal cancer metastasis by destroying the vascular endothelial barrier. Carcinogenesis 2023; 44:356-367. [PMID: 36939367 DOI: 10.1093/carcin/bgad013] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 03/05/2023] [Accepted: 03/17/2023] [Indexed: 03/21/2023] Open
Abstract
Metastasis is the leading cause of colorectal cancer treatment failure and mortality. Communication between endothelium and tumor cells in the tumor microenvironment is required for cancer metastasis. Tumor-derived exosomes have been shown to increase vascular permeability by delivering microRNA (miRNA) to vascular endothelial cells, facilitating cancer metastasis. The mechanism by which Epithelial-mesenchymal transition (EMT) tumor cell-derived exosomes influence vascular permeability remains unknown. MicroRNA-29a (miR-29a) expression is up-regulated in colorectal cancer (CRC) tissues, which is clinically significant in metastasis. Exosomal miR-29a secreted by EMT-CRC cells has been found to decrease the expression of Zonula occlusion 1 (ZO-1), Claudin-5, and Occludin via targeting Kruppel-like factor 4 (KLF4). In vitro co-culture investigations further revealed that EMT-cancer cells release exosomal miR-29a, which alters vascular endothelial permeability. Furthermore, exosomal miR-29a promoted liver metastases in CRC mice. Our findings demonstrate that EMT-CRC cells may transport exosomal miR-29a to endothelial cells in the tumor microenvironment (TME). As a result, increased vascular permeability promotes the development and metastasis of CRC. Exosomal miR-29a has the potential to be a predictive marker for tumor metastasis as well as a viable therapeutic target for CRC.
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Affiliation(s)
- Keshu Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Ziyang Di
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Dongdong Shi
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Chunxiao Zhang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Jialin Song
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Yan Fang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Sihao Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Zhenxian Xiang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Weisong Zhang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
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14
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Ge X, Zhou Z, Yang S, Ye W, Wang Z, Wang J, Xiao C, Cui M, Zhou J, Zhu Y, Wang R, Gao Y, Wang H, Tang P, Zhou X, Wang C, Cai W. Exosomal USP13 derived from microvascular endothelial cells regulates immune microenvironment and improves functional recovery after spinal cord injury by stabilizing IκBα. Cell Biosci 2023; 13:55. [PMID: 36915206 PMCID: PMC10012460 DOI: 10.1186/s13578-023-01011-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
Spinal cord injury (SCI) can result in irreversible sensory and motor disability with no effective treatment currently. After SCI, infiltrated macrophages accumulate in epicenter through destructed blood-spinal cord barrier (BSCB). Further, great majority of macrophages are preferentially polarized to M1 phenotype, with only a few transient M2 phenotype. The purpose of this study was to explore roles of vascular endothelial cells in microglia/macrophages polarization and the underlying mechanism. Lipopolysaccharide (LPS) was used to pretreat BV2 microglia and RAW264.7 macrophages followed by administration of conditioned medium from microvascular endothelial cell line bEnd.3 cells (ECM). Analyses were then performed to determine the effects of exosomes on microglia/macrophages polarization and mitochondrial function. The findings demonstrated that administration of ECM shifted microglia/macrophages towards M2 polarization, ameliorated mitochondrial impairment, and reduced reactive oxygen species (ROS) production in vitro. Notably, administration of GW4869, an exosomal secretion inhibitor, significantly reversed these observed benefits. Further results revealed that exosomes derived from bEnd.3 cells (Exos) promote motor rehabilitation and M2 polarization of microglia/macrophages in vivo. Ubiquitin-specific protease 13 (USP13) was shown to be significantly enriched in BV2 microglia treated with Exos. USP13 binds to, deubiquitinates and stabilizes the NF-κB inhibitor alpha (IκBα), thus regulating microglia/macrophages polarization. Administration of the selective IκBα inhibitor betulinic acid (BA) inhibited the beneficial effect of Exos in vivo. These findings uncovered the potential mechanism underlying the communications between vascular endothelial cells and microglia/macrophages after SCI. In addition, this study indicates exosomes might be a promising therapeutic strategy for SCI treatment.
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Affiliation(s)
- Xuhui Ge
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Zheng Zhou
- Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Siting Yang
- Department of Anesthesiology and Nursing, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Wu Ye
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Zhuanghui Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jiaxing Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Chenyu Xiao
- Department of Human Anatomy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Min Cui
- Department of Human Anatomy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Jiawen Zhou
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 211198, China
| | - Yufeng Zhu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Rixiao Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Yu Gao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Haofan Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Pengyu Tang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xuhui Zhou
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Ce Wang
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Weihua Cai
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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15
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Zhang J, Huang D, Lan X, Deng D, Li J, Zhang D, Li Y, Zhong T, Peng S. Application of small extracellular vesicles in the diagnosis and prognosis of nasopharyngeal carcinoma. Front Cell Dev Biol 2023; 11:1100941. [PMID: 36968209 PMCID: PMC10036369 DOI: 10.3389/fcell.2023.1100941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/02/2023] [Indexed: 03/12/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelium of the nasopharynx. The disease is insidious, and most patients are diagnosed at the advanced stage, resulting in poor prognosis. Early diagnosis is important to reduce NPC mortality. Small extracellular vesicles (sEVs) are rich in a variety of bioactive molecules, such as proteins, nucleic acids, and lipids, which can participate in the physiological and pathological regulation of the body by affecting the function of target cells. Numerous studies have shown that some RNAs and proteins in sEVs of tumor origin have a key role in the development of NPC and are potential candidates for malignancy detection. Studying the relationship between the cargoes of these sEVs and NPC may help in the diagnosis of the disease. Here in this review, we summarize the application of sEVs as biomarkers in the diagnosis of NPC and their role in NPC metastasis and prognosis. In addition, we discuss possible future applications and limitations of sEVs as biomarkers.
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Affiliation(s)
- Jiali Zhang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Defa Huang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xianbin Lan
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Dongming Deng
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jijing Li
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Dongzhi Zhang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yue Li
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Tianyu Zhong, ; Shaoping Peng,
| | - Shaoping Peng
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Department of Otolaryngology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Tianyu Zhong, ; Shaoping Peng,
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16
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Zhao L, Yu L, Wang X, He J, Zhu X, Zhang R, Yang A. Mechanisms of function and clinical potential of exosomes in esophageal squamous cell carcinoma. Cancer Lett 2023; 553:215993. [PMID: 36328162 DOI: 10.1016/j.canlet.2022.215993] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/05/2022] [Accepted: 10/27/2022] [Indexed: 11/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.
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Affiliation(s)
- Lijun Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lili Yu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiangpeng Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jangtao He
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiaofei Zhu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Rui Zhang
- The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Angang Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China; The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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17
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Yang X, Yu F, Huang G, Ni Y, Zhang T, Zou Z, Meng M. Exosomal miR-133a-3p promotes the growth and metastasis of lung cancer cells following incomplete microwave ablation. Int J Hyperthermia 2023; 40:2190065. [PMID: 37031959 DOI: 10.1080/02656736.2023.2190065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2023] Open
Abstract
PURPOSE Exosomal miRNAs play key roles in various biological processes such as cell proliferation, angiogenesis, migration and invasion. We explored whether exosomal miRNAs can promote local recurrence (LR) of lung tumors following incomplete microwave ablation (MWA) therapy. METHODS Exosomal miRNA profiles before and after incomplete MWA in lung cancer (LC) patients with LR (n = 3) were sequenced and compared. The differentially expressed miRNAs of interest were validated in clinical samples (n = 10) and MWA-treated cells using RT-qPCR analysis. Target genes of the miRNAs were predicted and validated. The biological functions of miRNAs in proliferation, angiogenesis and metastasis of A549 cells were evaluated in vitro and in vivo. RESULTS A total of 270 miRNAs (243 upregulated and 27 downregulated) were differentially expressed after incomplete MWA in patients with local recurrence. Upregulation of miR-133a-3p after MWA was validated in the cells and clinical samples. Cell functional experiments suggested that miR-133a-3p overexpression derived from serum exosomes increased cell viability, migration and invasion ability, tube formation activity and proliferation of A549 cells. Sirtuin 1 (SIRT1) was identified as a target gene for miR-133a-3p. Moreover, miR-133a-3p delivered by exosomes significantly promoted tumor growth, paralleled by reduced SIRT1 expression in a subcutaneous tumorigenesis animal model and increased the number of lung nodules by tail vein metastasis in vivo. CONCLUSION Exosomal miR-133a-3p overexpression promoted tumor growth and metastasis following MWA and could be a promising biomarker for LC recurrence after incomplete MWA.
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Affiliation(s)
- Xia Yang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Fangyuan Yu
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guanghui Huang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yang Ni
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tiehong Zhang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhigeng Zou
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Min Meng
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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18
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Jafari A, Karimabadi K, Rahimi A, Rostaminasab G, Khazaei M, Rezakhani L, Ahmadi jouybari T. The Emerging Role of Exosomal miRNAs as Biomarkers for Early Cancer Detection: A Comprehensive Literature Review. Technol Cancer Res Treat 2023; 22:15330338231205999. [PMID: 37817634 PMCID: PMC10566290 DOI: 10.1177/15330338231205999] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 09/10/2023] [Accepted: 09/13/2023] [Indexed: 10/12/2023] Open
Abstract
A significant number of cancer-related deaths are recorded globally each year, despite attempts to cure this illness. Medical science is working to develop new medication therapies as well as to find ways to identify this illness as early as possible, even using noninvasive techniques. Early detection of cancer can greatly aid its treatment. Studies into cancer diagnosis and therapy have recently shifted their focus to exosome (EXO) biomarkers, which comprise numerous RNA and proteins. EXOs are minuscule goblet vesicles that have a width of 30 to 140 nm and are released by a variety of cells, including immune, stem, and tumor cells, as well as bodily fluids. According to a growing body of research, EXOs, and cancer appear to be related. EXOs from tumors play a role in the genetic information transfer between tumor and basal cells, which controls angiogenesis and fosters tumor development and spread. To identify malignant activities early on, microRNAs (miRNAs) from cancers can be extracted from circulatory system EXOs. Specific markers can be used to identify cancer-derived EXOs containing miRNAs, which may be more reliable and precise for early detection. Conventional solid biopsy has become increasingly limited as precision and personalized medicine has advanced, while liquid biopsy offers a viable platform for noninvasive diagnosis and prognosis. Therefore, the use of body fluids such as serum, plasma, urine, and salivary secretions can help find cancer biomarkers using technologies related to EXOs.
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Affiliation(s)
- Ali Jafari
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Keyvan Karimabadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Aso Rahimi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gelavizh Rostaminasab
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Touraj Ahmadi jouybari
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
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19
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Xu D, Di K, Fan B, Wu J, Gu X, Sun Y, Khan A, Li P, Li Z. MicroRNAs in extracellular vesicles: Sorting mechanisms, diagnostic value, isolation, and detection technology. Front Bioeng Biotechnol 2022; 10:948959. [PMID: 36324901 PMCID: PMC9618890 DOI: 10.3389/fbioe.2022.948959] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of short, single-stranded, noncoding RNAs, with a length of about 18–22 nucleotides. Extracellular vesicles (EVs) are derived from cells and play a vital role in the development of diseases and can be used as biomarkers for liquid biopsy, as they are the carriers of miRNA. Existing studies have found that most of the functions of miRNA are mainly realized through intercellular transmission of EVs, which can protect and sort miRNAs. Meanwhile, detection sensitivity and specificity of EV-derived miRNA are higher than those of conventional serum biomarkers. In recent years, EVs have been expected to become a new marker for liquid biopsy. This review summarizes recent progress in several aspects of EVs, including sorting mechanisms, diagnostic value, and technology for isolation of EVs and detection of EV-derived miRNAs. In addition, the study reviews challenges and future research avenues in the field of EVs, providing a basis for the application of EV-derived miRNAs as a disease marker to be used in clinical diagnosis and even for the development of point-of-care testing (POCT) platforms.
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Affiliation(s)
- Dongjie Xu
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Kaili Di
- Department of Laboratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Boyue Fan
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jie Wu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xinrui Gu
- Department of Laboratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yifan Sun
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Adeel Khan
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education (Southeast University), Southeast University, Nanjing, China
| | - Peng Li
- College of Animal Science, Yangtze University, Jingzhou, China
- *Correspondence: Peng Li, ; Zhiyang Li,
| | - Zhiyang Li
- Department of Laboratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Peng Li, ; Zhiyang Li,
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20
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Mao L, Li YD, Chen RL, Li G, Zhou XX, Song F, Wu C, Hu Y, Hong YX, Dang X, Li GR, Wang Y. Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy. J Nanobiotechnology 2022; 20:435. [PMID: 36195937 PMCID: PMC9531502 DOI: 10.1186/s12951-022-01630-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/09/2022] [Indexed: 12/04/2022] Open
Abstract
Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of β-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.
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Affiliation(s)
- Liang Mao
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
| | - Yun-Da Li
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Ruo-Lan Chen
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Gang Li
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Xiao-Xia Zhou
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Fei Song
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Chan Wu
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Yu Hu
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Yi-Xiang Hong
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Xitong Dang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
| | - Gui-Rong Li
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.,Nanjing Amaigh Pharma Limited, Nanjing, 210032, China
| | - Yan Wang
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.
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21
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Yi X, Huang D, Li Z, Wang X, Yang T, Zhao M, Wu J, Zhong T. The role and application of small extracellular vesicles in breast cancer. Front Oncol 2022; 12:980404. [PMID: 36185265 PMCID: PMC9515427 DOI: 10.3389/fonc.2022.980404] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related deaths in women worldwide. Currently, patients’ survival remains a challenge in BC due to the lack of effective targeted therapies and the difficult condition of patients with higher aggressiveness, metastasis and drug resistance. Small extracellular vesicles (sEVs), which are nanoscale vesicles with lipid bilayer envelopes released by various cell types in physiological and pathological conditions, play an important role in biological information transfer between cells. There is growing evidence that BC cell-derived sEVs may contribute to the establishment of a favorable microenvironment that supports cancer cells proliferation, invasion and metastasis. Moreover, sEVs provide a versatile platform not only for the diagnosis but also as a delivery vehicle for drugs. This review provides an overview of current new developments regarding the involvement of sEVs in BC pathogenesis, including tumor proliferation, invasion, metastasis, immune evasion, and drug resistance. In addition, sEVs act as messenger carriers carrying a variety of biomolecules such as proteins, nucleic acids, lipids and metabolites, making them as potential liquid biopsy biomarkers for BC diagnosis and prognosis. We also described the clinical applications of BC derived sEVs associated MiRs in the diagnosis and treatment of BC along with ongoing clinical trials which will assist future scientific endeavors in a more organized direction.
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Affiliation(s)
- Xiaomei Yi
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhengzhe Li
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoxing Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tong Yang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Minghong Zhao
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jiyang Wu
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Tianyu Zhong,
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22
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Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, Sabet S, Khoshbakht MA, Hashemi M, Hushmandi K, Sethi G, Zarrabi A, Kumar AP, Tan SC, Papadakis M, Alexiou A, Islam MA, Mostafavi E, Ashrafizadeh M. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol 2022; 15:83. [PMID: 35765040 PMCID: PMC9238168 DOI: 10.1186/s13045-022-01305-4] [Citation(s) in RCA: 313] [Impact Index Per Article: 104.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/13/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohamad Javad Naghdi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sina Sabet
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Amin Khoshbakht
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey.
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23
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Dhar R, Mallik S, Devi A. Exosomal microRNAs (exoMIRs): micromolecules with macro impact in oral cancer. 3 Biotech 2022; 12:155. [DOI: 10.1007/s13205-022-03217-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 05/31/2022] [Indexed: 12/16/2022] Open
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24
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Yang K, Zhou Q, Qiao B, Shao B, Hu S, Wang G, Yuan W, Sun Z. Exosome-derived noncoding RNAs: Function, mechanism, and application in tumor angiogenesis. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:983-997. [PMID: 35317280 PMCID: PMC8905256 DOI: 10.1016/j.omtn.2022.01.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Exosomes are extracellular vesicles released by various cell types that perform various biological functions, mainly mediating communication between different cells, especially those active in cancer. Noncoding RNAs (ncRNAs), of which there are many types, were recently identified as enriched and stable in the exocrine region and play various roles in the occurrence and progression of cancer. Abnormal angiogenesis has been confirmed to be related to human cancer. An increasing number of studies have shown that exosome-derived ncRNAs play an important role in tumor angiogenesis. In this review, we briefly outline the characteristics of exosomes, ncRNAs, and tumor angiogenesis. Then, the mechanism of the impact of exosome-derived ncRNAs on tumor angiogenesis is analyzed from various angles. In addition, we focus on the regulatory role of exosome-derived ncRNAs in angiogenesis in different types of cancer. Furthermore, we emphasize the potential role of exosome-derived ncRNAs as biomarkers in cancer diagnosis and prognosis and therapeutic targets in the treatment of tumors.
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Affiliation(s)
- Kangkang Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Bingbing Qiao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Bo Shao
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Shengyun Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Guixian Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
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25
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Chowdhury SG, Ray R, Bhattacharya D, Karmakar P. DNA damage induced cellular senescence and it’s PTEN-armed exosomes—the warriors against prostate carcinoma cells. Med Oncol 2022; 39:34. [DOI: 10.1007/s12032-021-01614-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/19/2021] [Indexed: 11/27/2022]
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26
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N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer. Int J Oncol 2022; 60:14. [PMID: 35014676 PMCID: PMC8759347 DOI: 10.3892/ijo.2022.5304] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/24/2021] [Indexed: 12/11/2022] Open
Abstract
Resistance to 5‑Fluorouracil (5‑FU) is a frequent occurrence in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) from cancer‑associated fibroblasts (CAFs)‑secreted exosomes have been associated with 5‑FU sensitivity. The potential molecular mechanism of CAFs‑exosomal miRNAs in CRC remains unclear. The aim of the present study was to elucidate the role of exosomal miRNAs in 5‑FU sensitivity in CRC. Exosomes derived from CAFs were extracted. Exosomal miR‑181d‑5p was identified as a miRNA associated with 5‑FU sensitivity. The putative function of exosomal miR‑181d‑5p was evaluated by ethynyl‑2‑deoxyuridine staining, flow cytometry, RNA immunoprecipitation, luciferase reporter assay, tumor xenograft formation, reverse transcription‑quantitative PCR and western blot analysis. Modification of miR‑181d‑5p by the RNA N6‑methyladenosine (m6A) methyltransferase like (METTL)3 was examined by m6A methylation analysis. The results indicated that m6A modification and METTL3 expression were upregulated in CRC patients. METTL3‑dependent m6A methylation promoted the miR‑181b‑5p process by DiGeorge Syndrome Critical Region 8 (DGCR8) in CAFs. CAFs‑derived exosomes inhibited 5‑FU sensitivity in CRC cells through the METTL3/miR‑181d‑5p axis. A mechanistic study revealed that miR‑181d‑5p directly targeted neurocalcin δ (NCALD) to inhibit the 5‑FU sensitivity of CRC cells. Patients with higher NCALD levels exhibited a higher survival rate. Taken together, METTL3‑dependent m6A methylation was upregulated in CRC to promote the processing of miR‑181d‑5p by DGCR8. This led to increased miR‑181d‑5p expression, which inhibited the 5‑FU sensitivity of CRC cells by targeting NCALD. The results of the present study provided novel insight into exosomal microRNAs in 5‑FU sensitivity in CRC cells. Furthermore, exosomal miR‑181d‑5p may represent a potential prognostic marker for CRC.
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27
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Ishraq Bari SM, Hossain FB, Nestorova GG. Advances in Biosensors Technology for Detection and Characterization of Extracellular Vesicles. SENSORS (BASEL, SWITZERLAND) 2021; 21:7645. [PMID: 34833721 PMCID: PMC8621354 DOI: 10.3390/s21227645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/11/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
Exosomes are extracellular vehicles (EVs) that encapsulate genomic and proteomic material from the cell of origin that can be used as biomarkers for non-invasive disease diagnostics in point of care settings. The efficient and accurate detection, quantification, and molecular profiling of exosomes are crucial for the accurate identification of disease biomarkers. Conventional isolation methods, while well-established, provide the co-purification of proteins and other types of EVs. Exosome purification, characterization, and OMICS analysis are performed separately, which increases the complexity, duration, and cost of the process. Due to these constraints, the point-of-care and personalized analysis of exosomes are limited in clinical settings. Lab-on-a-chip biosensing has enabled the integration of isolation and characterization processes in a single platform. The presented review discusses recent advancements in biosensing technology for the separation and detection of exosomes. Fluorescent, colorimetric, electrochemical, magnetic, and surface plasmon resonance technologies have been developed for the quantification of exosomes in biological fluids. Size-exclusion filtration, immunoaffinity, electroactive, and acoustic-fluid-based technologies were successfully applied for the on-chip isolation of exosomes. The advancement of biosensing technology for the detection of exosomes provides better sensitivity and a reduced signal-to-noise ratio. The key challenge for the integration of clinical settings remains the lack of capabilities for on-chip genomic and proteomic analysis.
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Affiliation(s)
| | - Faria Binte Hossain
- Molecular Science and Nanotechnology, Louisiana Tech University, Ruston, LA 71272, USA;
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28
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Lyu Z, Yang M, Yang T, Ma M, Yang Z. Metal-Regulatory Transcription Factor-1 Targeted by miR-148a-3p Is Implicated in Human Hepatocellular Carcinoma Progression. Front Oncol 2021; 11:700649. [PMID: 34660270 PMCID: PMC8511627 DOI: 10.3389/fonc.2021.700649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/06/2021] [Indexed: 12/24/2022] Open
Abstract
Metal-regulatory transcription factor-1 (MTF-1) is of importance in maintaining metal homeostasis. Copper exposure considerably stimulates the proliferation of hepatocellular carcinoma (HCC) cells with enhanced MTF-1 expression. However, the underlying molecular mechanisms have not been completely elucidated. In this study, we utilized different approaches to investigate the potential role of MTF-1 involved in HCC progression. The expression levels of MTF-1 and miR-148a-3p were determined using real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemistry. The interaction of MTF-1 with apurinic apyrimidinic endonuclease/redox effector factor 1 (APE/Ref-1) or miR-148a-3p was determined using immunoprecipitation or dual-luciferase reporter assay, respectively. Cell viability and metastatic ability were evaluated using colony formation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound scratch, and Transwell assays, and apoptotic cells were detected by flow cytometry. The biological functions of MTF-1 and miR-148a-3p were also determined using a xenograft mouse model. MTF-1 expression was upregulated in HCC cells and was associated with poor survival and recurrence. MTF-1 overexpression enhanced the proliferation and metastatic potential of HCC cells. Further mechanistic analyses demonstrated that MTF-1 bound to APE/Ref-1 and that MTF-1 is a direct target of miR-148-3p, which inversely regulated MTF-1 transcription activity. MiR-148a-3p overexpression effectively inhibited HCC cell proliferation and metastasis stimulated by MTF-1, with increased apoptosis. There was a decrease in miR-148a-3p expression in exosomes isolated from the plasma of patients with HCC and HCC cell culture supernatants. Co-incubation of HCC cells with exosomes from hepatocyte-conditioned media inhibited cell migration and caused apoptosis. The in vivo study revealed slow growth of MTF-1-knockdown and miR-148a-3p-overexpressing Hep3B-derived xenografts, with reduced tumor volume and weight compared with the control group. Collectively, these findings implicate MTF-1 as a modulator of HCC tumorigenesis and progression. Selective targeting towards exosomal miR-148a-3p, which might contribute to the negative regulation of MTF-1 at least partially in HCC, demonstrates therapeutic benefits for patients with HCC.
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Affiliation(s)
- Zhuozhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mingyu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tan Yang
- Department of Infectious Diseases, Jining First People's Hospital, Jining, China
| | - Mingze Ma
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Bondhopadhyay B, Sisodiya S, Alzahrani FA, Bakhrebah MA, Chikara A, Kasherwal V, Khan A, Rani J, Dar SA, Akhter N, Tanwar P, Agrawal U, Hussain S. Exosomes: A Forthcoming Era of Breast Cancer Therapeutics. Cancers (Basel) 2021; 13:4672. [PMID: 34572899 PMCID: PMC8464658 DOI: 10.3390/cancers13184672] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/20/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.
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Affiliation(s)
- Banashree Bondhopadhyay
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
| | - Sandeep Sisodiya
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 411004, India
| | - Faisal Abdulrahman Alzahrani
- Department of Biochemistry, Faculty of Science, Embryonic Stem Cells Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Muhammed A. Bakhrebah
- Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia;
| | - Atul Chikara
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 411004, India
| | - Vishakha Kasherwal
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, India
| | - Asiya Khan
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201313, India;
- Laboratory Oncology Unit, Dr. Bheem Rao Ambedkar Institute Rotary Cancer Hospital (Dr. BRA-IRCH), All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110023, India;
| | - Jyoti Rani
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
| | - Sajad Ahmad Dar
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan 45142, Saudi Arabia;
| | - Naseem Akhter
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha 65411, Saudi Arabia;
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. Bheem Rao Ambedkar Institute Rotary Cancer Hospital (Dr. BRA-IRCH), All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110023, India;
| | - Usha Agrawal
- ICMR-National Institute of Pathology, New Delhi 110029, India;
| | - Showket Hussain
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
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30
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Jing Z, Chen K, Gong L. The Significance of Exosomes in Pathogenesis, Diagnosis, and Treatment of Esophageal Cancer. Int J Nanomedicine 2021; 16:6115-6127. [PMID: 34511909 PMCID: PMC8423492 DOI: 10.2147/ijn.s321555] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/16/2021] [Indexed: 12/21/2022] Open
Abstract
Esophageal cancer is one of the most common malignancy in China with high mortality. Understanding pathogenesis and identifying early diagnosis biomarkers can significantly improve the prognosis of patients with esophageal cancer. Exosomes are small vesicular structures containing a variety of components (including DNA, RNA, and proteins) mediating cell-to-cell material exchange and signal communication. Growing evidences have shown that exosomes and its components are involved in growth, metastasis and angiogenesis in cancer, and could also be used as diagnostic and prognostic markers. In this review, we summarized recent progress to elucidate the significance of exosomes in the esophageal cancer progression, microenvironment remodeling, therapeutic resistance, and immunosuppression. We also discuss the utility of exosomes as diagnostic and prognostic biomarkers and therapeutic tool in esophageal cancer.
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Affiliation(s)
- Zhao Jing
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Kai Chen
- Department of Cardiovascular and Thoracic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Ling Gong
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China
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31
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Maleki M, Golchin A, Javadi S, Khelghati N, Morovat P, Asemi Z, Alemi F, Vaghari-Tabari M, Yousefi B, Majidinia M. Role of exosomal miRNA in chemotherapy resistance of Colorectal cancer: A systematic review. Chem Biol Drug Des 2021; 101:1096-1112. [PMID: 34480511 DOI: 10.1111/cbdd.13947] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/25/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022]
Abstract
The third most common malignancy has been identified as Colorectal cancer (CRC) that conducive to death in most cases. Chemoresistance is a common obstacle to CRC treatment. Circulating exosomal microRNAs (miRNAs) have been shown to reverse chemo-resistance and are promising biomarkers for CRC. The capacity of engineered exosomes to cross biological barriers and deliver functional miRNAs could be used to achieve these proposes. The object of this review is the investigation of the role of exosomal miRNA in the chemo-resistance, diagnosis, and prognosis of CRC. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, electronic databases, PubMed, EMBASE, Web of Science, Scopus were searched from January 1990 to November 2020. Ultimately, eight articles included five in vitro (16 cell lines) and three in vivo examinations. Three studies demonstrated that increasing or decreasing mRNA expression was associated with increasing and decreasing cell proliferation in vitro. The presence of miRNA in two studies increased the sensitivity of the drug and exhibited a considerable growth inhibitory effect on cancer cell proliferation. The apoptotic rate was significantly increased in four studies by increased mRNA expression and reduced mrna expression. Tumor volume of xenograft models in three studies suppressed by antitumor miRNA activity. In contrast, anti-miRNA activity in one study decreased the tumor volume. Exosomal miRNAs can be regulators of chemo-resistance and predict adverse outcomes in CRC patients. In sum, exosomes containing miRNAs can be a promising biomarker for the prognosis and diagnosis of CRC. Subsequent research should be a focus on delineating the function of exosomal miRNA before clinical use.
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Affiliation(s)
- Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asal Golchin
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Samira Javadi
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nafiseh Khelghati
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Pejman Morovat
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Vaghari-Tabari
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
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32
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Prieto-Vila M, Yoshioka Y, Ochiya T. Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer. Front Cell Dev Biol 2021; 9:620498. [PMID: 34527665 PMCID: PMC8435577 DOI: 10.3389/fcell.2021.620498] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.
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Affiliation(s)
| | | | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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33
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Yu Y, Li W, Mao L, Peng W, Long D, Li D, Zhou R, Dang X. Genetically engineered exosomes display RVG peptide and selectively enrich a neprilysin variant: a potential formulation for the treatment of Alzheimer's disease. J Drug Target 2021; 29:1128-1138. [PMID: 34182845 DOI: 10.1080/1061186x.2021.1929257] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Exosome is a promising next generation nano-based drug delivery vehicle. However, the unknown molecular mechanisms underlying its natural tissue tropism and the relatively low quantity of naturally enriched molecules of therapeutic value hamper exosome's clinical application. The aim of the research was to create a targeted and highly efficacious exosome formulation for the treatment of Alzheimer's disease (AD). Genetic engineering techniques combined with co-transfection of parental cells were employed to create an exosome formulation that displays RVG peptide on its surface targeting α7-nAChR and simultaneously enriches a neprilysin variant with increased specificity and efficacy in degrading β amyloid peptide (Aβ). The exosome formulation was preferentially internalised into cell lines in an α7-nAChR expression level-dependent manner. When incubated with Aβ-producing N2a cells, it significantly decreased intracellular and secreted Aβ40 levels, a potency that is superior to exosomes derived from adipose-derived stem cell. When systemically administered into mice, the exosome formulation was preferentially targeted to the hippocampus region of the brain and significantly decreased the expression of proinflammatory genes, IL1α, TNFα and NF-κB, and simultaneously increased the expression of anti-inflammatory gene, IL10. Our exosome formulation may be explored as an over-the-counter treatment for AD.
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Affiliation(s)
- Yonghe Yu
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Wei Li
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Liang Mao
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Wanling Peng
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Dandan Long
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Dongmei Li
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China
| | - Rui Zhou
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China.,Department of Cardiology, Shaanxi Institute for Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xitong Dang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Luzhou, China.,Department of Cardiovascular Medicine, The 1st Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
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34
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Xu X, Zhang D, Ding W, Wang W, Jin N, Ding Z. NDV related exosomes enhance NDV replication through exporting NLRX1 mRNA. Vet Microbiol 2021; 260:109167. [PMID: 34274763 DOI: 10.1016/j.vetmic.2021.109167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 06/27/2021] [Indexed: 10/21/2022]
Abstract
Virulent Newcastle disease virus (NDV) is a violent infection in avian species. The understanding of its pathogenic mechanism is consistently evolving along with the development of molecular biological advancement. Exosomes derived from NDV infected cells (NDV Ex) were reported to promote virus replication through transportation of viral proteins and miRNAs. However, the function of mRNAs in NDV Ex remains unknown. In this study, a novel mechanism of NDV Ex to facilitate NDV infection was explored. Through transcriptome analysis, seven immune related genes were found to up-regulate in NDV Ex. Among them, NLRX1 mRNA was notably enriched in NDV Ex, and decreased inside the cells after virulent NDV infection. Further investigation suggested that NLRX1 mRNA decrease was in accordance with the NLRX1 protein expression reduction. This process can be reversed by the inhibition of exosome release. Therefore, NDV infection could utilize NDV Ex to export NLRX1 mRNA and reduce cellular NLRX1 protein. As NLRX1 is a crucial anti-viral protein of MAVS signal pathway, and NDV Ex transported NLRX1 cannot counteract its function in recipient cells, it can be concluded that NDV could benefit its replication through exporting NLRX1 mRNA to relieve the anti-viral pressure on its survival.
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Affiliation(s)
- Xiaohong Xu
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China; College of Basic Medical Science, Jilin University, Changchun, 130021, China
| | - Di Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China
| | - Wei Ding
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China
| | - Weiqi Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China
| | - Ningyi Jin
- College of Basic Medical Science, Jilin University, Changchun, 130021, China.
| | - Zhuang Ding
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China.
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35
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Wu BQ, Li CH, Zhang ML, Nie MH. [microRNA-1 gene delivery mediated by exosomes suppresses CAL-27 cell proliferation]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2021; 39:136-142. [PMID: 33834667 DOI: 10.7518/hxkq.2021.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVES This study aims to construct endogenous exosomes abundantly loaded with miR-1 and investigate the role of exosome-mediated microRNA-1 (miR-1) delivery on CAL-27 cell proliferation. METHODS Exosomes secreted by miR-1-overexpressing HEK293 cells (miR1-EXO) were purified via ultracentrifugation and subjected to transmission electron microscopy, nanoparticle analysis, Western blot analysis, and quantitative polymerase chain reaction (qPCR). CAL-27 cells were cocultured with exosomes secreted by HEK293 cells (CON-EXO) and miR1-EXO and equivalent phosphate buffer saline. The intracellular transport of exosomes was measured by using immunofluorescence, the expression of miR-1 and its target gene MET were investigated via qPCR, CAL-27 cell proliferation was measured through MTT assay, and cell cycle state was determined by applying flow cytometry. RESULTS Electron microscopy revealed that miR1-EXO and CON-EXO were spherical or cup-shaped with an average diameter of approximately 110 nm. The well-known exosome markers CD9, Tsg101, and Alix were enriched. The expression of miR-1 in miR1-EXO was higher than that in CON-EXO (285.80±14.33 vs 1.00±0.06, P<0.000 1). After coculture with CAL-27 cells, miR1-EXO was internalized and unloaded miR-1 into CAL-27 cells. After coculture with miR1-EXO, the expression of miR-1 in CAL-27 cells was upregulated, whereas that of MET, the target gene of miR-1, was suppressed and the proliferation of CAL-27 cells was inhibited significantly. Normal oral keratinocyte cell proliferation was negligibly affected after coculture with miR1-EXO. CONCLUSIONS Exosomes secreted from miR1-EXO cells could load abundant miR-1. Exosomal miR-1 delivered into CAL-27 cells by using miR1-EXO suppressed the expression of MET mRNA and inhibited cell proliferation.
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Affiliation(s)
- Bao-Qin Wu
- Orofacial Reconstruction and Regeneration Laboratory, School of Stomatology of Southwest Medical University, Luzhou 646000, China.,Dept. of Periodontal and Oral Medicine, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou 646000, China
| | - Chun-Hui Li
- Orofacial Reconstruction and Regeneration Laboratory, School of Stomatology of Southwest Medical University, Luzhou 646000, China.,Dept. of Periodontal and Oral Medicine, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou 646000, China
| | - Meng-Lian Zhang
- Orofacial Reconstruction and Regeneration Laboratory, School of Stomatology of Southwest Medical University, Luzhou 646000, China
| | - Min-Hai Nie
- Orofacial Reconstruction and Regeneration Laboratory, School of Stomatology of Southwest Medical University, Luzhou 646000, China.,Dept. of Periodontal and Oral Medicine, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou 646000, China
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36
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Jiang L, Zhang Y, Li B, Kang M, Yang Z, Lin C, Hu K, Wei Z, Xu M, Mi J, Wang R, Wu F. miRNAs derived from circulating small extracellular vesicles as diagnostic biomarkers for nasopharyngeal carcinoma. Cancer Sci 2021; 112:2393-2404. [PMID: 33728743 PMCID: PMC8177774 DOI: 10.1111/cas.14883] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/13/2022] Open
Abstract
The microRNAs (miRNAs) in circulating small extracellular vesicles (sEVs) have been suggested as potential biomarkers in cancer diagnosis. This study was designed to evaluate the circulating sEV‐derived miRNAs as biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC). We compared the miRNA profiles in plasma‐derived sEVs between 16 patients with NPC and 5 healthy controls (HCs). A distinct set of miRNAs that were differentially expressed between patients with NPC and HCs was determined by means of integrative bioinformatics approaches. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis revealed that the target genes of the differentially expressed miRNAs (DEMs) were mainly involved in cancer‐associated signaling pathways. Seven representative DEMs were selected and further validated in an additional 60 patients with NPC and 40 HCs using quantitative reverse‐transcription PCR analysis (qRT‐PCR). Receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of the sEV‐miRNA‐based model for diagnosis. The 3 miRNA‐based model, comprising miR‐134‐5p, miR‐205‐5p, and miR‐409‐3p, showed good discriminating power with an area under the curve (AUC) value of 0.88 in the training set and 0.91 in the validation set. Furthermore, the diagnostic model had an excellent classification ability to distinguish patients with NPC at different clinical stages or Epstein‐Barr virus infection status from HCs. In conclusion, our findings indicated that sEV‐derived miRNA levels were altered in the plasma of patients with NPC in comparison with those in HCs. The model based on the 3 sEV‐derived miRNAs could potentially act as an alternative or complementary approach for diagnosing NPC. This study was designed to evaluate circulating sEV‐derived miRNAs as biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC). Our findings indicated that sEV‐derived miRNA levels were altered in the plasma of patients with NPC compared with those in HCs. The model based on the 3 sEV‐derived miRNAs could potentially act as an alternative or complementary approach for diagnosing NPC. ![]()
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Affiliation(s)
- Li Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yong Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bo Li
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Min Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhendong Yang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chunyu Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Kai Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhuxin Wei
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Meng Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jinglin Mi
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Rensheng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fang Wu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Alshehri B. Plant-derived xenomiRs and cancer: Cross-kingdom gene regulation. Saudi J Biol Sci 2021; 28:2408-2422. [PMID: 33911956 PMCID: PMC8071896 DOI: 10.1016/j.sjbs.2021.01.039] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 12/18/2022] Open
Abstract
Exosomal microRNAs (miRNAs) critically regulate several major intracellular and metabolic activities, including cancer evolution. Currently, increasing evidence indicates that exosome harbor and transport these miRNAs from donor cells to neighboring and distantly related recipient cells, often in a cross-species manner. Several studies have reported that plant-based miRNAs can be absorbed into the serum of humans, where they hinder the expression of human disease-related genes. Moreover, few recent studies have demonstrated the role of these xenomiRs in cancer development and progression. However, the cross-kingdom gene regulation hypothesis remains highly debatable, and many follow up studies fail to reproduce the same. There are reports that show no effect of plant-derived miRNAs on mammalian cancers. The foremost cause of this controversy remains the lack of reproducibility of the results. Here, we reassess the latest developments in the field of cross-kingdom transference of miRNAs, emphasizing on the role of the diet-based xenomiRs on cancer progression.
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Affiliation(s)
- Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
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Lin YC, Chen TH, Huang YM, Wei PL, Lin JC. Involvement of microRNA in Solid Cancer: Role and Regulatory Mechanisms. Biomedicines 2021; 9:biomedicines9040343. [PMID: 33805515 PMCID: PMC8065716 DOI: 10.3390/biomedicines9040343] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.
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Affiliation(s)
- Ying-Chin Lin
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Tso-Hsiao Chen
- Division of Nephrology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Yu-Min Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastrointestinal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
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Akoto T, Saini S. Role of Exosomes in Prostate Cancer Metastasis. Int J Mol Sci 2021; 22:3528. [PMID: 33805398 PMCID: PMC8036381 DOI: 10.3390/ijms22073528] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer remains a life-threatening disease among men worldwide. The majority of PCa-related mortality results from metastatic disease that is characterized by metastasis of prostate tumor cells to various distant organs, such as lung, liver, and bone. Bone metastasis is most common in prostate cancer with osteoblastic and osteolytic lesions. The precise mechanisms underlying PCa metastasis are still being delineated. Intercellular communication is a key feature underlying prostate cancer progression and metastasis. There exists local signaling between prostate cancer cells and cells within the primary tumor microenvironment (TME), in addition to long range signaling wherein tumor cells communicate with sites of future metastases to promote the formation of pre-metastatic niches (PMN) to augment the growth of disseminated tumor cells upon metastasis. Over the last decade, exosomes/ extracellular vesicles have been demonstrated to be involved in such signaling. Exosomes are nanosized extracellular vesicles (EVs), between 30 and 150 nm in thickness, that originate and are released from cells after multivesicular bodies (MVB) fuse with the plasma membrane. These vesicles consist of lipid bilayer membrane enclosing a cargo of biomolecules, including proteins, lipids, RNA, and DNA. Exosomes mediate intercellular communication by transferring their cargo to recipient cells to modulate target cellular functions. In this review, we discuss the contribution of exosomes/extracellular vesicles in prostate cancer progression, in pre-metastatic niche establishment, and in organ-specific metastases. In addition, we briefly discuss the clinical significance of exosomes as biomarkers and therapeutic agents.
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Affiliation(s)
- Theresa Akoto
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA;
| | - Sharanjot Saini
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
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Zheng Y, Luo Y, Chen X, Li H, Huang B, Zhou B, Zhu L, Kang X, Geng W. The role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors. Mol Cancer 2021; 20:49. [PMID: 33673851 PMCID: PMC7934508 DOI: 10.1186/s12943-021-01341-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/23/2021] [Indexed: 12/24/2022] Open
Abstract
Neural tumors can generally be divided into central nervous system tumors and peripheral nervous tumors. Because this type of tumor is located in the nerve, even benign tumors are often difficult to remove by surgery. In addition, the majority of neural tumors are malignant, and it is particular the same for the central nervous system tumors. Even treated with the means such as chemotherapy and radiotherapy, they are also difficult to completely cure. In recent years, an increasingly number of studies have focused on the use of mRNA to treat tumors, representing an emerging gene therapy. The use of mRNA can use the expression of some functional proteins for the treatment of genetic disorders or tissue repair, and it can also be applied to immunotherapy through the expression of antigens, antibodies or receptors. Therefore, although these therapies are not fully-fledged enough, they have a broad research prospect. In addition, there are many ways to treat tumors using mRNA vaccines and exosomes carrying mRNA, which have drawn much attention. In this study, we reviewed the current research on the role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors, and examine the future research prospects of mRNA in neural tumors and the opportunities and challenges that will arise in the future application of clinical treatment.
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Affiliation(s)
- Yiyang Zheng
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.,School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Yanyan Luo
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Xixi Chen
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Huiting Li
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Baojun Huang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Baofeng Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Liqing Zhu
- Department of clinical laboratory, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
| | - Xianhui Kang
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Wujun Geng
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
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Roles of Bile-Derived Exosomes in Hepatobiliary Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8743409. [PMID: 33511212 PMCID: PMC7822672 DOI: 10.1155/2021/8743409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022]
Abstract
Exosomes are vesicles with a diameter of 30-150 nm produced by living cells and secreted into the extracellular matrix. Exosomes mediate cellular communication by carrying active molecules, such as nucleic acids, proteins, and liposomes. Although exosomes are found in various body fluids, little is known about bile-derived exosomes. This review is the first to summarize the methods of bile storage and isolation of biliary exosomes, highlighting the roles of bile-derived exosomes, especially exosomal noncoding RNAs, in physiological and disease states and discussing their potential clinical applications.
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Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases. Cancers (Basel) 2020; 13:cancers13010084. [PMID: 33396739 PMCID: PMC7795854 DOI: 10.3390/cancers13010084] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents. Abstract Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application.
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Noh GT, Kwon J, Kim J, Park M, Choi DW, Cho KA, Woo SY, Oh BY, Lee KY, Lee RA. Verification of the role of exosomal microRNA in colorectal tumorigenesis using human colorectal cancer cell lines. PLoS One 2020; 15:e0242057. [PMID: 33175885 PMCID: PMC7657557 DOI: 10.1371/journal.pone.0242057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a group of small membranous vesicles that are shed into the extracellular environment by tumoral or non-tumoral cells and contribute to cellular communication by delivering micro RNAs (miRNAs). In this study, we aimed to evaluate the role of exosomal miRNAs from colorectal cancer cell lines in tumorigenesis, by affecting cancer-associated fibroblasts (CAFs), which are vital constituents of the tumor microenvironment. To analyze the effect of exosomal miRNA on the tumor microenvironment, migration of the monocytic cell line THP-1 was evaluated via Transwell migration assay using CAFs isolated from colon cancer patients. The migration assay was performed with CAFs ± CCL7-blocking antibody and CAFs that were treated with exosomes isolated from colon cancer cell lines. To identify the associated exosomal miRNAs, miRNA sequencing and quantitative reverse transcription polymerase chain reaction were performed. The migration assay revealed that THP-1 migration was decreased in CCL7-blocking antibody-expressing and exosome-treated CAFs. Colon cancer cell lines contained miRNA let-7d in secreted exosomes targeting the chemokine CCL7. Exosomes from colorectal cancer cell lines affected CCL7 secretion from CAFs, possibly via the miRNA let-7d, and interfered with the migration of CCR2+ monocytic THP-1 cells in vitro.
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Affiliation(s)
- Gyoung Tae Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Jiyun Kwon
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Jungwoo Kim
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Minhwa Park
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Da-Won Choi
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Kyung-Ah Cho
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - So-Youn Woo
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Bo-Young Oh
- Department of Surgery, Hallym University College of Medicine, Seoul, South Korea
| | - Kang Young Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul, South Korea
- * E-mail:
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Kok VC, Yu CC. Cancer-Derived Exosomes: Their Role in Cancer Biology and Biomarker Development. Int J Nanomedicine 2020; 15:8019-8036. [PMID: 33116515 PMCID: PMC7585279 DOI: 10.2147/ijn.s272378] [Citation(s) in RCA: 277] [Impact Index Per Article: 55.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/29/2020] [Indexed: 02/05/2023] Open
Abstract
Exosomes are a subset of tiny extracellular vesicles manufactured by all cells and are present in all body fluids. They are produced actively in tumor cells, which are released and utilized to facilitate tumor growth. Their characteristics enable them to assist major cancer hallmarks, leveraged by cancer cells in fostering cancer growth and spread while implementing ways to escape elimination from the host environment. This review updates on the latest progress on the roles of cancer-derived exosomes, of 30-100 nm in size, in deregulating paracrine trafficking in the tumor microenvironment and circulation. Thus, exosomes are being exploited in diagnostic biomarker development, with its potential in clinical applications as therapeutic targets utilized in exosome-based nanoparticle drug delivery strategies for cancer therapy. Ongoing studies were retrieved from PubMed® and Scopus database and ClinicalTrials.gov registry for review, highlighting how cancer cells from entirely different cell lines rely on genetic information carried by their exosomes for homotypic and heterotypic intercellular communications in the microenvironment to favor proliferation and invasion, while establishing a pre-metastatic niche in welcoming cancer cells' arrival. We will elaborate on the trafficking of tumor-derived exosomes in fostering cancer proliferation, invasion, and metastasis in hematopoietic (leukemia and myeloma), epithelial (breast cancer), and mesenchymal (soft tissue sarcoma and osteosarcoma) cancers. Cancer-derived exosomal trafficking is observed in several types of liquid or solid tumors, confirming their role as cancer hallmark enabler. Their enriched genetic signals arising from their characteristic DNA, RNA, microRNA, and lncRNA, along with specific gene expression profiles, protein, or lipid composition carried by the exosomal cargo shed into blood, saliva, urine, ascites, and cervicovaginal lavage, are being studied as a diagnostic, prognostic, or predictive cancer biomarker. We reveal the latest research efforts in exploiting the use of nanoparticles to improve the overall cancer diagnostic capability in the clinic.
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Affiliation(s)
- Victor C Kok
- Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Cheng-Chia Yu
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
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Choi JU, Park IK, Lee YK, Hwang SR. The Biological Function and Therapeutic Potential of Exosomes in Cancer: Exosomes as Efficient Nanocommunicators for Cancer Therapy. Int J Mol Sci 2020; 21:ijms21197363. [PMID: 33028046 PMCID: PMC7582692 DOI: 10.3390/ijms21197363] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/30/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer therapeutics must be delivered to their targets for improving efficacy and reducing toxicity, though they encounter physiological barriers in the tumor microenvironment. They also face limitations associated with genetic instability and dynamic changes of surface proteins in cancer cells. Nanosized exosomes generated from the endosomal compartment, however, transfer their cargo to the recipient cells and mediate the intercellular communication, which affects malignancy progression, tumor immunity, and chemoresistance. In this review, we give an overview of exosomes' biological aspects and therapeutic potential as diagnostic biomarkers and drug delivery vehicles for oncotherapy. Furthermore, we discuss whether exosomes could contribute to personalized cancer immunotherapy drug design as efficient nanocommunicators.
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Affiliation(s)
- Jeong Uk Choi
- College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea;
| | - In-Kyu Park
- Department of Biomedical Sciences, Chonnam National University Medical School, 322 Seoyang-ro, Hwasun 58128, Korea;
| | - Yong-Kyu Lee
- Department of Chemical and Biological Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, Chungbuk 27469, Korea;
| | - Seung Rim Hwang
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
- Department of Biomedical Sciences, Graduate School, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
- Correspondence: ; Tel.: +82-62-230-6365
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Monsellato I, Garibaldi E, Cassinotti E, Baldari L, Boni L, Elmore U, Delpini R, Rosati R, Perinotti R, Alongi F, Bertocchi E, Gori S, Ruffo G, Pernazza G, Pulighe F, De Nisco C, Morpurgo E, Contardo T, Mammano E, Perna F, Menegatti B, Coratti A, Buccianti P, Balestri R, Ceccarelli C, Cavaliere D, Solaini L, Ercolani G, Traverso E, Fusco V, Torri V, Orecchia S. Expression levels of circulating miRNAs as biomarkers during multimodal treatment of rectal cancer - TiMiSNAR-mirna: a substudy of the TiMiSNAR Trial (NCT03962088). Trials 2020; 21:678. [PMID: 32711544 PMCID: PMC7382047 DOI: 10.1186/s13063-020-04568-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 07/02/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Neoadjuvant chemoradiotherapy followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading and lymph node status helped to visualize individual tumor sensitivity to chemoradiotherapy, retrospectively. As the response to neoadjuvant chemoradiotherapy is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed. MicroRNAs are currently under investigation to serve as blood-based biomarkers. To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken. The aim of the study is to investigate the role of circulating miRNAs as biomarkers in those patients included in the TiMiSNAR Trial (NCT03465982). This is a biomolecular substudy of TiMiSNAR Trial (NCT03962088). METHODS All included patients in the TiMiSNAR Trial are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery, and after adjuvant chemotherapy whenever indicated. DISCUSSION TiMiSNAR-MIRNA will evaluate the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pathological complete response. Moreover, the study will evaluate the role of liquid biopsies in the monitoring of treatment, correlate changes in expression levels of miRNA following complete surgical resection with disease-free survival, and evaluate the relation between changes in miRNA during surveillance and tumor relapse. TRIAL REGISTRATION Clinicaltrials.gov NCT03962088 . Registered on 23 May 2019.
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Affiliation(s)
- Igor Monsellato
- Department of Surgery, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Via Venezia 16, 15121 Alessandria, Italy
| | - Elisabetta Garibaldi
- Department of Radiation Oncology, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Elisa Cassinotti
- Department of Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Ludovica Baldari
- Department of Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Luigi Boni
- Department of Surgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Ugo Elmore
- Ospedale San raffaele IRCCS, Milan, Italy
| | | | | | | | | | | | | | | | | | | | | | - Emilio Morpurgo
- Ospedale Civile Pietro Cosma, Camposampiero/Ospedale Sant’Antonio, Padova, Italy
| | - Tania Contardo
- Ospedale Civile Pietro Cosma, Camposampiero, Padova, Italy
| | - Enzo Mammano
- Ospedale Civile Pietro Cosma, Camposampiero/Ospedale Sant’Antonio, Padova, Italy
| | - Federico Perna
- Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | | | - Andrea Coratti
- Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | | | | | | | | | | | | | - Elena Traverso
- Department of Oncology, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Vittorio Fusco
- Department of Oncology, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Valter Torri
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Sara Orecchia
- Department of Pathology, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
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Yue B, Yang H, Wang J, Ru W, Wu J, Huang Y, Lan X, Lei C, Chen H. Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Prolif 2020; 53:e12857. [PMID: 32578911 PMCID: PMC7377932 DOI: 10.1111/cpr.12857] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/02/2020] [Accepted: 05/16/2020] [Indexed: 12/17/2022] Open
Abstract
Exosomes are membrane-bound extracellular vesicles that are produced in the endosomal compartment of most mammalian cell types and then released. Exosomes are effective carriers for the intercellular material transfer of material that can influence a series of physiological and pathological processes in recipient cells. Among loaded cargoes, non-coding RNAs (ncRNAs) vary for the exosome-producing cell and its homeostatic state, and characterization of the biogenesis and secretion of exosomal ncRNAs and the functions of these ncRNAs in skeletal muscle myogenesis remain preliminary. In this review, we will describe what is currently known of exosome biogenesis, release and uptake of exosomal ncRNAs, as well as the varied functions of exosomal miRNAs in skeletal muscle myogenesis.
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Affiliation(s)
- Binglin Yue
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Haiyan Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Jian Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Wenxiu Ru
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Jiyao Wu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yongzheng Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xianyong Lan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Hong Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Roudnicky F, Poyet C, Buser L, Saba K, Wild P, Otto VI, Detmar M. Characterization of Tumor Blood Vasculature Expression of Human Invasive Bladder Cancer by Laser Capture Microdissection and Transcriptional Profiling. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1960-1970. [PMID: 32585158 DOI: 10.1016/j.ajpath.2020.05.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/16/2020] [Accepted: 05/27/2020] [Indexed: 01/23/2023]
Abstract
Tumor-associated blood vessels differ from normal vessels and play key roles in tumor progression. We aimed to identify biomolecules that are expressed differentially in human bladder cancer-associated blood vessels to find novel biomarkers and mechanisms involved in tumor-associated angiogenesis. The transcriptome of tumor blood vasculature from human invasive bladder carcinoma (I-BLCA) and normal bladder tissue vasculature was compared using differential expression and unsupervised hierarchical clustering analyses. Pathway analysis identified up-regulation of genes involved in the proliferation, cell cycle, angiogenesis, inflammation, and transforming growth factor-β signaling in tumor blood vasculature. A common consensus gene expression signature was identified between bladder cancer tumor blood vasculature with tumor blood vasculature of other solid cancers, which correlated with the overall survival of patients with several of the solid cancers investigated in The Cancer Genome Atlas data set. In bladder tumor blood vasculature, the secreted factor angiopoietin-like protein 2 (ANGPTL2), was confirmed to be up-regulated by quantitative RT-PCR and immunohistochemical staining. The up-regulation of ANGPTL2 in plasma was also observed in non-invasive bladder carcinoma and I-BLCA. We semiquantitatively analyzed expression of ANGPTL2 in tissue microarrays from I-BLCA and surprisingly found an opposite correlation between staining intensity and progression-free survival. Our results indicate that ANGPTL2 might serve as a potential biomarker to predict progression-free survival in I-BLCA.
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Affiliation(s)
- Filip Roudnicky
- Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
| | - Cedric Poyet
- Department of Urology, University Hospital Zurich, Zürich, Switzerland
| | - Lorenz Buser
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zürich, Switzerland
| | - Karim Saba
- Department of Urology, University Hospital Zurich, Zürich, Switzerland
| | - Peter Wild
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zürich, Switzerland
| | - Vivianne I Otto
- Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland.
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Wang Y, Zhang Y, Cai G, Li Q. Exosomes as Actively Targeted Nanocarriers for Cancer Therapy. Int J Nanomedicine 2020; 15:4257-4273. [PMID: 32606676 PMCID: PMC7306454 DOI: 10.2147/ijn.s239548] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 05/25/2020] [Indexed: 12/11/2022] Open
Abstract
In recent years, it has been found that exosomes can be used as nanocarriers, which can be used in the treatment of tumors by carrying contents. The exosomes are derived from the secretion of the organism's own cells and are characterized by a phospholipid bilayer structure and a small particle size. These characteristics guarantee that the exosomes can carry a wide range of tumor drugs, deliver the drug to the cancer, and reduce or eliminate the tumor drug band. The toxic side effects were significantly eliminated; meanwhile, the therapeutic effects of the drug on the tumor were remarkably improved. This paper reviewed the strategies and drugs presented by different scholars for the treatment of tumors based on the drugs carried by exosomes.
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Affiliation(s)
- Yan Wang
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai201203, People’s Republic of China
| | - Yingru Zhang
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai201203, People’s Republic of China
| | - Gang Cai
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai201203, People’s Republic of China
| | - Qi Li
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai201203, People’s Republic of China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai201203, People’s Republic of China
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Turdo A, Porcelli G, D’Accardo C, Di Franco S, Verona F, Forte S, Giuffrida D, Memeo L, Todaro M, Stassi G. Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities. Cancers (Basel) 2020; 12:E1436. [PMID: 32486505 PMCID: PMC7352619 DOI: 10.3390/cancers12061436] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells-termed cancer stem cells (CSCs)-which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.
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Affiliation(s)
- Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Gaetana Porcelli
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Caterina D’Accardo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Francesco Verona
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Dario Giuffrida
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
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