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Xu K, Wu Q, Lingyun Z, Nguyen R, Safri F, Yang W, Xu Y, Ye Y, Kwan HY, Wang Q, Liang X, Shiddiky MJA, Warkiani ME, George J, Bao J, Qiao L. Extracellular vesicles as a promising platform of precision medicine in liver cancer. Pharmacol Res 2025:107800. [PMID: 40419123 DOI: 10.1016/j.phrs.2025.107800] [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: 02/19/2025] [Revised: 05/19/2025] [Accepted: 05/22/2025] [Indexed: 05/28/2025]
Abstract
Extracellular vesicles (EVs) are natural carriers of biological information and play pivotal roles in intercellular communication. EVs are biocompatible, have low immunogenicity, and are capable of traversing biological barriers, making them ideal tools for disease diagnosis and therapy. Despite their promising prospects, the full realization of EVs potential faces several challenges. This article aims to comprehensively review the biological and molecular features of EVs, their applications in liver cancer and possible underlying mechanisms, and the critical challenges affecting the clinical translation of EVs-based therapies in liver cancer.
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Affiliation(s)
- Keyang Xu
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qibiao Wu
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Zhao Lingyun
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Romario Nguyen
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Fatema Safri
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - William Yang
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Yikun Xu
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Yun Ye
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, China
| | - Hiu Yee Kwan
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, China
| | - Qiang Wang
- Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
| | - Xiuming Liang
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine Karolinska Institute, Stockholm, Sweden
| | - Muhammad J A Shiddiky
- Rural Health Research Institute (RHRI), Charles Sturt University, Orange NSW 2800, Australia
| | - Majid E Warkiani
- School of Biomedical Engineering, the University of Technology Sydney, Ultimo NSW 2007, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Jianfeng Bao
- Hangzhou Xixi Hospital affiliated to Zhejiang Chinese Medical University, Zhejiang, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia.
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Yu Q, Ye S, Chen M, Sun P, Weng N. A novel function for exosomes in depression. Life Sci 2025; 369:123558. [PMID: 40089099 DOI: 10.1016/j.lfs.2025.123558] [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: 01/02/2025] [Revised: 03/01/2025] [Accepted: 03/08/2025] [Indexed: 03/17/2025]
Abstract
Exosomes are a class of extracellular vesicles that encompass a diverse array of bioactive molecules, including proteins, lipids, mRNA, and microRNA(miRNA). Virtually all cell types release exosomes under both physiological and pathological conditions. In addition to electrical and chemical signals, exosomes are an alternative route of signaling between cells in the brain. In the brain, they are involved in processes such as synaptic plasticity, neuronal stress response, intercellular communication, and neurogenesis. A number of studies have shown that exosomes regulate the occurrence and development of depression by participating in the regulation of hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, immune inflammatory response and other mechanisms, showing that they may become potential biological agents for the diagnosis and treatment of depression. In addition, exosomes have the ability to easily cross the blood-brain barrier, making them ideal drug or molecular delivery tools for the central nervous system. Engineered exosomes have good brain targeting ability, and their research in central nervous system diseases has begun to emerge. However, the molecular pathways involved in the pathogenesis of depression remain unknown, and further studies are needed to fully understand the role of exosomes in the development or improvement of depression. Therefore, in this review, we mainly focus on the diagnostic performance and therapeutic effect of exosomes in depression, and explore the advantages of exosomes as biomarkers and gene delivery vectors for depression.
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Affiliation(s)
- Qingying Yu
- School of Pharmacy, Shandong University of Chinese Medicine, Jinan 250000, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Shuyi Ye
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Mengxue Chen
- Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, China
| | - Peng Sun
- Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250000, China.
| | - Ning Weng
- Department of Chinese Medicine, Shandong Mental Health Center, Shandong University, Jinan, China.
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Nishiwada S, Nakamura K, Ozu N, Terai T, Kohara Y, Nagai M, Sakata T, Doi S, Matsuo Y, Yasuda S, Tanaka T, Sho M. An axon guidance-related microRNA panel identifies perivascular plexus local recurrence following curative surgery in patients with pancreatic cancer. J Gastroenterol 2025:10.1007/s00535-025-02260-w. [PMID: 40347276 DOI: 10.1007/s00535-025-02260-w] [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: 12/10/2024] [Accepted: 04/28/2025] [Indexed: 05/12/2025]
Abstract
BACKGROUND Complete oncological local control is essential for a potential cure in patients with pancreatic ductal adenocarcinoma (PDAC), but predicting local recurrence following curative surgery remains clinically challenging. In this study, we performed comprehensive biomarker discovery to identify an Axon guidance-related miRNA panel (AGMP) for risk-stratification of perivascular plexus recurrence (PPR) following curative surgery in patients with PDAC. METHODS To identify axon guidance-related microRNAs, we performed the pathway-miRNA interaction analysis using the miRPathDB2.0. Subsequently, the predictive performance of the miRNAs was trained and validated in three independent clinical surgically resected sample cohorts and one pretreatment blood sample cohort with different disease statuses [upfront surgery cohort: n = 162 (training: n = 103, internal validation: n = 59), neoadjuvant chemoradiotherapy (NACRT) cohort: n = 217, arterial invasion cohort: n = 62, pretreatment blood sample cohort: n = 53]. RESULTS The pathway-miRNA interaction analysis identified 13 miRNAs related to axon guidance pathway. Subsequently, we trained a 13-miRNA risk-prediction model, AGMP, which robustly distinguished PPR after surgery in the training cohort (AUC = 0.95). The AGMP was successfully validated in three independent cohorts (AUC: validation = 0.94, NACRT = 0.94, Arterial invasion = 0.90). Furthermore, we additionally validated the performance of AGMP in a pretreatment blood cohort, which again confirmed the robustness of risk-stratification for PPR (AUC = 0.86). CONCLUSIONS We developed a novel biomarker, AGMP that demonstrated remarkable predictive performance for PPR following curative surgery in patients with PDAC; highlighting the clinical importance of the nerve-cancer cross-talk and the hopefulness as a guidepost for designing future clinical and basic research to establish individualized treatment strategies.
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Affiliation(s)
- Satoshi Nishiwada
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
- Department of Surgery, Minami-Nara General Medical Center, Nara, Japan
| | - Kota Nakamura
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Naoki Ozu
- Institute for Clinical and Translational Science, Nara Medical University Hospital, Nara, Japan
| | - Taichi Terai
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yuichiro Kohara
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Minako Nagai
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Takeshi Sakata
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Shunsuke Doi
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yasuko Matsuo
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Satoshi Yasuda
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Toshihiro Tanaka
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Nara, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
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Xia HF, Wang XL, Zhang HJ, Wang KM, Zhang LZ, Yang Y, Shi X, Chen G. PCBP2-dependent secretion of miRNAs via extracellular vesicles contributes to the EGFR-driven angiogenesis. Theranostics 2025; 15:1255-1271. [PMID: 39816681 PMCID: PMC11729547 DOI: 10.7150/thno.102391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 12/04/2024] [Indexed: 01/18/2025] Open
Abstract
Rationale: The EGFR-driven angiogenesis is crucial in solid tumors, particularly through the delivery of biomolecules via extracellular vesicles (EVs), but the mechanism by which EGFR regulates EV cargo is still unclear. Methods: First, cell co-culture and murine tumor models were employed to examine the impact of EGFR overexpression on the pro-angiogenic properties of small EVs (sEVs) derived from oral squamous cell carcinoma (OSCC). Small RNA sequencing was then used to compare the miRNA profiles of OSCC-sEVs with and without EGFR overexpression, followed by functional enrichment and motif analyses of the differentially expressed miRNAs. Next, miRNA pull-down assays were conducted to identify potential molecules involved in sorting these miRNAs. Finally, the role of the candidate sorting protein was validated using existing public database, tissue samples, cell lines, and murine tumor models. Results: EGFR overexpression significantly enhances the pro-angiogenic effects of OSCC-sEVs, accompanied by a marked increase in the content of nucleic acid cargo carried in these sEVs. Small-RNA sequencing identified a group of miRNAs that were significantly enriched in OSCC-sEVs due to EGFR overexpression, which primarily functioned in angiogenesis and shared a characteristic "GGGU" motif. EGFR overexpression also strengthened the binding of PCBP2 with miRNAs containing this "GGGU" motif, thereby promoting their secretion through sEVs to support tumor angiogenesis. Mechanismly, EGFR overexpression upregulates PCBP2 protein content by activating its transcription rather than regulating the mRNA stability in OSCC cells. Additionally, depletion of PCBP2 impaired the EGFR-driven tumor angiogenesis by inhibiting the secretion of pro-angiogenic miRNAs through sEVs. Conclusions: EGFR boosts PCBP2 expression via transcriptional regulation, which then promotes the loading of specific miRNAs into sEVs by binding to the "GGGU" motif, thereby driving tumor angiogenesis.
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Affiliation(s)
- Hou-Fu Xia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Xiao-Le Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - He-Jing Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Kui-Ming Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Lin-Zhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yang Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Xin Shi
- Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Gang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China
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Chen S, Li L, Xu W, Xie N, Xu H, Zhou Y, Zou Y, Yi K, Zhang Z. CircMIB1 inhibits glioma development and progression through a competing endogenous RNA interaction network. Front Mol Biosci 2024; 11:1513919. [PMID: 39698112 PMCID: PMC11652353 DOI: 10.3389/fmolb.2024.1513919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction The critical role of circular RNAs as non-coding RNAs in glioma has been extensively investigated. Therefore, we aimed to explore the role and potential molecular mechanisms of circRNA-mind bomb homolog 1 (circMIB1) in gliomas. Methods RNA sequencing was used to analyze the expression profiles of circRNAs in glioma tissues and normal brain tissues. Quantitative real-time polymerase chain reaction was implemented to examine the levels of circMIB1 in glioma cells and tissues. The circMIB1 was identified as a cyclic RNA molecule by DNA nucleic acid electrophoresis and ribonuclease R assay. The relationship between circMIB1 expression and the prognosis of glioma patients and its potential as a biomarker were analysed using Kaplan-Meier, Receiver operating characteristic curves, and Principal component analysis. Bioinformatics analysis predicted the miRNAs that bind to circMIB1 and their downstream targets, and analysed the functions of these genes. Results Firstly, a novel circRNA molecule termed circMIB1 was identified and validated by RNA sequencing. The expression of circMIB1 was significantly downregulated in glioma cells and tissues, and was closely associated with the tumor grade and survival prognosis of patients with glioma. Hence, it may be useful as a biomarker for glioma. Secondly, it was predicted that circMIB1 binds to hsa-miR-1290 based on bioinformatics analysis, which was significantly upregulated in glioma cells and tissues, and correlated with the tumor grade and overall survival of patients. Thirdly, through a series of bioinformatics analyses identified six genes downstream of hsa-miR-1290 that were significantly associated with glioma expression and prognosis, these genes are associated with cell cycle, cell necrosis and cell circadian rhythms. Discussion CircMIB1 may play a role in inhibiting glioma development through the hsa-miR-1290 competitive endogenous RNA interaction network, these findings provide new ideas and directions for the diagnosis and treatment of glioma.
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Affiliation(s)
- Simin Chen
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Longping Li
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Wei Xu
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Nanjiao Xie
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Huiting Xu
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Yongjun Zhou
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Ying Zou
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Kai Yi
- Department of Clinical Laboratory, Yiyang Central Hospital, Yiyang, Hunan, China
| | - Zuping Zhang
- School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan, China
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Kouroumalis E, Tsomidis I, Voumvouraki A. Extracellular Vesicles in Viral Liver Diseases. Viruses 2024; 16:1785. [PMID: 39599900 PMCID: PMC11598962 DOI: 10.3390/v16111785] [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: 09/30/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.
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Affiliation(s)
- Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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Hendley AM, Ashe S, Urano A, Ng M, Phu TA, Peng XL, Luan C, Finger AM, Jang GH, Kerper NR, Berrios DI, Jin D, Lee J, Riahi IR, Gbenedio OM, Chung C, Roose JP, Yeh JJ, Gallinger S, Biankin AV, O'Kane GM, Ntranos V, Chang DK, Dawson DW, Kim GE, Weaver VM, Raffai RL, Hebrok M. nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.23.614610. [PMID: 39399775 PMCID: PMC11468832 DOI: 10.1101/2024.09.23.614610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression. Graphical abstract
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Zhao J, Ma Y, Zheng X, Sun Z, Lin H, Du C, Cao J. Bladder cancer: non-coding RNAs and exosomal non-coding RNAs. Funct Integr Genomics 2024; 24:147. [PMID: 39217254 DOI: 10.1007/s10142-024-01433-9] [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: 07/28/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Bladder cancer (BCa) is a highly prevalent type of cancer worldwide, and it is responsible for numerous deaths and cases of disease. Due to the diverse nature of this disease, it is necessary to conduct significant research that delves deeper into the molecular aspects, to potentially discover novel diagnostic and therapeutic approaches. Lately, there has been a significant increase in the focus on non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), due to their growing recognition for their involvement in the progression and manifestation of BCa. The interest in exosomes has greatly grown due to their potential for transporting a diverse array of active substances, including proteins, nucleic acids, carbohydrates, and lipids. The combination of these components differs based on the specific cell and its condition. Research indicates that using exosomes could have considerable advantages in identifying and forecasting BCa, offering a less invasive alternative. The distinctive arrangement of the lipid bilayer membrane found in exosomes is what makes them particularly effective for administering treatments aimed at managing cancer. In this review, we have tried to summarize different ncRNAs that are involved in BCa pathogenesis. Moreover, we highlighted the role of exosomal ncRNAs in BCa.
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Affiliation(s)
- Jingang Zhao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Yangyang Ma
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Xiaodong Zheng
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Zhen Sun
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Hongxiang Lin
- Department of Urology, Ganzhou Donghe Hospital, Ganzhou, 341000, Jiang'xi, China
| | - Chuanjun Du
- Department of Urology, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, 310009, Zhe'jiang, China
| | - Jing Cao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China.
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Fekry B, Ugartemendia L, Esnaola NF, Goetzl L. Extracellular Vesicles, Circadian Rhythms, and Cancer: A Comprehensive Review with Emphasis on Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2552. [PMID: 39061191 PMCID: PMC11274441 DOI: 10.3390/cancers16142552] [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: 06/20/2024] [Revised: 07/12/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
This review comprehensively explores the complex interplay between extracellular vesicles (ECVs)/exosomes and circadian rhythms, with a focus on the role of this interaction in hepatocellular carcinoma (HCC). Exosomes are nanovesicles derived from cells that facilitate intercellular communication by transporting bioactive molecules such as proteins, lipids, and RNA/DNA species. ECVs are implicated in a range of diseases, where they play crucial roles in signaling between cells and their surrounding environment. In the setting of cancer, ECVs are known to influence cancer initiation and progression. The scope of this review extends to all cancer types, synthesizing existing knowledge on the various roles of ECVs. A unique aspect of this review is the emphasis on the circadian-controlled release and composition of exosomes, highlighting their potential as biomarkers for early cancer detection and monitoring metastasis. We also discuss how circadian rhythms affect multiple cancer-related pathways, proposing that disruptions in the circadian clock can alter tumor development and treatment response. Additionally, this review delves into the influence of circadian clock components on ECV biogenesis and their impact on reshaping the tumor microenvironment, a key component driving HCC progression. Finally, we address the potential clinical applications of ECVs, particularly their use as diagnostic tools and drug delivery vehicles, while considering the challenges associated with clinical implementation.
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Affiliation(s)
- Baharan Fekry
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Lierni Ugartemendia
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Nestor F. Esnaola
- Division of Surgical Oncology and Gastrointestinal Surgery, Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA;
| | - Laura Goetzl
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
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Li A, Xie J, Lv L, Zheng Z, Yang W, Zhuo W, Yang S, Cai D, Duan J, Liu P, Min J, Wei J. RPL9 acts as an oncogene by shuttling miRNAs through exosomes in human hepatocellular carcinoma cells. Int J Oncol 2024; 64:58. [PMID: 38639179 PMCID: PMC11087036 DOI: 10.3892/ijo.2024.5646] [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: 10/19/2023] [Accepted: 02/05/2024] [Indexed: 04/20/2024] Open
Abstract
The exosomal pathway is an essential mechanism that regulates the abnormal content of microRNAs (miRNAs) in hepatocellular carcinoma (HCC). The directional transport of miRNAs requires the assistance of RNA‑binding proteins (RBPs). The present study found that RBPs participate in the regulation of miRNA content through the exosomal pathway in HCC cells. First, differential protein expression profiles in the serum exosomes of patients with HCC and benign liver disease were detected using mass spectrometry. The results revealed that ribosomal protein L9 (RPL9) was highly expressed in serum exosomes of patients with HCC. In addition, the downregulation of RPL9 markedly suppressed the proliferation, migration and invasion of HCC cells and reduced the biological activity of HCC‑derived exosomes. In addition, using miRNA microarrays, the changes in exosomal miRNA profiles in HCC cells caused by RPL9 knockdown were examined. miR‑24‑3p and miR‑185‑5p were most differentially expressed, as verified by reverse transcription‑quantitative PCR. Additionally, using RNA immunoprecipitation, it was found that RPL9 was directly bound to the two miRNAs and immunofluorescence assays confirmed that RPL9 was able to carry miRNAs into recipient cells via exosomes. Overexpression of miR‑24‑3p in cells increased the accumulation of miR‑24‑3p in exosomes and simultaneously upregulated RPL9. Excessive expression of miR‑24‑3p in exosomes also increased their bioactivity. Exosome‑mediated miRNA regulation and transfer require the involvement of RBPs. RPL9 functions as an oncogene, can directly bind to specific miRNAs and can be co‑transported to receptor cells through exosomes, thereby exerting its biological functions. These findings provide a novel approach for modulating miRNA profiles in HCC.
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Affiliation(s)
- Ang Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Jiyan Xie
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036
| | - Lihong Lv
- Clinical Trial Institution of Pharmaceuticals and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Zhihua Zheng
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Weibang Yang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260
| | - Wenfeng Zhuo
- Department of Hepatobiliary Surgery, Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong 528406, P.R. China
| | - Sijia Yang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Diankui Cai
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Jinxin Duan
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Peiqing Liu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Jun Min
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
| | - Jinxing Wei
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120
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11
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Raghav A, Jeong GB. Nanoquercetin and Extracellular Vesicles as Potential Anticancer Therapeutics in Hepatocellular Carcinoma. Cells 2024; 13:638. [PMID: 38607076 PMCID: PMC11011524 DOI: 10.3390/cells13070638] [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: 11/29/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024] Open
Abstract
Despite world-class sophisticated technologies, robotics, artificial intelligence, and machine learning approaches, cancer-associated mortalities and morbidities have shown continuous increments posing a healthcare burden. Drug-based interventions were associated with systemic toxicities and several limitations. Natural bioactive compounds derived nanoformulations, especially nanoquercetin (nQ), are alternative options to overcome drug-associated limitations. Moreover, the EVs-based cargo targeted delivery of nQ can have enormous potential in treating hepatocellular carcinoma (HCC). EVs-based nQ delivery synergistically regulates and dysregulates several pathways, including NF-κB, p53, JAK/STAT, MAPK, Wnt/β-catenin, and PI3K/AKT, along with PBX3/ERK1/2/CDK2, and miRNAs intonation. Furthermore, discoveries on possible checkpoints of anticancer signaling pathways were studied, which might lead to the development of modified EVs infused with nQ for the development of innovative treatments for HCC. In this work, we abridged the control of such signaling systems using a synergetic strategy with EVs and nQ. The governing roles of extracellular vesicles controlling the expression of miRNAs were investigated, particularly in relation to HCC.
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Affiliation(s)
| | - Goo Bo Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea;
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12
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Dvilansky I, Altaras Y, Kamenetsky N, Nachmias D, Elia N. The human AAA-ATPase VPS4A isoform and its co-factor VTA1 have a unique function in regulating mammalian cytokinesis abscission. PLoS Biol 2024; 22:e3002327. [PMID: 38687820 PMCID: PMC11086821 DOI: 10.1371/journal.pbio.3002327] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 05/10/2024] [Accepted: 04/04/2024] [Indexed: 05/02/2024] Open
Abstract
Mutations in the human AAA-ATPase VPS4 isoform, VPS4A, cause severe neurodevelopmental defects and congenital dyserythropoietic anemia (CDA). VPS4 is a crucial component of the endosomal sorting complex required for transport (ESCRT) system, which drives membrane remodeling in numerous cellular processes, including receptor degradation, cell division, and neural pruning. Notably, while most organisms encode for a single VPS4 gene, human cells have 2 VPS4 paralogs, namely VPS4A and VPS4B, but the functional differences between these paralogs is mostly unknown. Here, we set out to investigate the role of the human VPS4 paralogs in cytokinetic abscission using a series of knockout cell lines. We found that VPS4A and VPS4B hold both overlapping and distinct roles in abscission. VPS4A depletion resulted in a more severe abscission delay than VPS4B and was found to be involved in earlier stages of abscission. Moreover, VPS4A and a monomeric-locked VPS4A mutant bound the abscission checkpoint proteins CHMP4C and ANCHR, while VPS4B did not, indicating a regulatory role for the VPS4A isoform in abscission. Depletion of VTA1, a co-factor of VPS4, disrupted VPS4A-ANCHR interactions and accelerated abscission, suggesting that VTA1 is also involved in the abscission regulation. Our findings reveal a dual role for VPS4A in abscission, one that is canonical and can be compensated by VPS4B, and another that is regulatory and may be delivered by its monomeric form. These observations provide a potential mechanistic explanation for the neurodevelopmental defects and other related disorders reported in VPS4A-mutated patients with a fully functional VPS4B paralog.
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Affiliation(s)
- Inbar Dvilansky
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Yarin Altaras
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Nikita Kamenetsky
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Dikla Nachmias
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Natalie Elia
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
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13
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Cunha E Rocha K, Ying W, Olefsky JM. Exosome-Mediated Impact on Systemic Metabolism. Annu Rev Physiol 2024; 86:225-253. [PMID: 38345906 DOI: 10.1146/annurev-physiol-042222-024535] [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: 02/15/2024]
Abstract
Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.
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Affiliation(s)
- Karina Cunha E Rocha
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
| | - Wei Ying
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
| | - Jerrold M Olefsky
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
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14
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Yao Y, Xu Y, Yu L, Xue T, Xiao Z, Tin P, Fung H, Ma H, Yun J, Yam JWP. NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma. Cancer Commun (Lond) 2024; 44:251-272. [PMID: 38152992 PMCID: PMC10876205 DOI: 10.1002/cac2.12515] [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: 03/06/2023] [Revised: 12/13/2023] [Accepted: 12/18/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Small extracellular vesicles (sEVs) mediate intercellular communication that contributes to hepatocellular carcinoma (HCC) progression via multifaceted pathways. The success of cell entry determines the effect of sEV on recipient cells. Here, we aimed to delineate the mechanisms underlying the uptake of sEV in HCC. METHODS Macropinocytosis was examined by the ability of cells to internalize dextran and sEV. Macropinocytosis was analyzed in Na(+)/H(+) exchanger 7 (NHE7)-knockdown and -overexpressing cells. The properties of cells were studied using functional assays. pH biosensor was used to evaluate the intracellular and endosomal pH. The expression of NHE7 in patients' liver tissues was examined by immunofluorescent staining. Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7. RESULTS The data revealed that macropinocytosis controlled the internalization of sEVs and their oncogenic effect on recipient cells. It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non-metastatic HCC cells. Attenuation of macropinocytic activity by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) limited the entry of sEVs and compromised cell aggressiveness. Mechanistically, we delineated that high level of NHE7, a sodium-hydrogen exchanger, alkalized intracellular pH and acidized endosomal pH, leading to the maturation of macropinosomes. Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis. Clinically, NHE7 expression was upregulated and linked to dismal prognosis of HCC. CONCLUSIONS This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells. Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC.
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Affiliation(s)
- Yue Yao
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- Department of Endocrinology and MetabolismSecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjingP. R. China
| | - Yi Xu
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- Department of Hepatopancreatobiliary SurgerySecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjingP. R. China
- State Key Laboratory of Oncology in South ChinaCancer Center of Sun Yat‐sen UniversityGuangzhouGuangdongP. R. China
| | - Liang Yu
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- Department of Hepatopancreatobiliary SurgerySecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjingP. R. China
| | - Ting‐Mao Xue
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- Department of Hepatobiliary Surgery IIZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Zhi‐Jie Xiao
- Scientific Research CenterThe Seventh Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdongP. R. China
| | - Pui‐Chi Tin
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
| | - Hiu‐Ling Fung
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
| | - Hoi‐Tang Ma
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongP. R. China
| | - Jing‐Ping Yun
- Department of PathologyCancer Center of Sun Yat‐sen UniversityGuangzhouGuangdongP. R. China
| | - Judy Wai Ping Yam
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP. R. China
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongP. R. China
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15
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Srinivas AN, Suresh D, Kaur S, Kumar DP. The promise of small particles: extracellular vesicles as biomarkers in liver pathology. J Physiol 2023; 601:4953-4971. [PMID: 35708653 DOI: 10.1113/jp283074] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/07/2022] [Indexed: 11/09/2022] Open
Abstract
Extracellular vesicles (EVs) are nanoscopic packages that are heterogeneous and bona fide players in hepatic physiology and pathology as they are involved in intercellular communication. EVs carrying bioactive cargoes rich in lipids, proteins or nucleic acids are implicated in the onset and progression of liver diseases. Liver pathology using liver biopsy has been assessed for several intricate conditions such as viral hepatitis, alcoholic and non-alcoholic fatty liver disease, hepatic malignancies and drug-induced liver injury. The lacunae, however, lie in early diagnosis and timely treatment of the above conditions, underscoring the need for non-invasive, accurate diagnostic tools that could replace the gold standard method of tissue biopsy. In this regard, EVs have emerged as promising candidates that could serve as potential biomarkers. In the last two decades, EVs, owing to their multifaceted charm in bringing out cell-free therapeutic responses and the ability of their cargoes to be applied to novel biomarkers, have drawn the great attention of researchers with the advancement and clinical application of liquid biopsy. In this review, we recapitulate the role of EVs and provide insights into the promising role of these small packages as biomarkers in liver pathology.
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Affiliation(s)
- Akshatha N Srinivas
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Diwakar Suresh
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Divya P Kumar
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
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16
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Chen H, Yao H, Chi J, Li C, Liu Y, Yang J, Yu J, Wang J, Ruan Y, Pi J, Xu JF. Engineered exosomes as drug and RNA co-delivery system: new hope for enhanced therapeutics? Front Bioeng Biotechnol 2023; 11:1254356. [PMID: 37823027 PMCID: PMC10562639 DOI: 10.3389/fbioe.2023.1254356] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/05/2023] [Indexed: 10/13/2023] Open
Abstract
Chemotherapy often faces some obstacles such as low targeting effects and drug resistance, which introduce the low therapeutic efficiency and strong side effects. Recent advances in nanotechnology allows the use of novel nanosystems for targeted drug delivery, although the chemically synthesized nanomaterials always show unexpected low biocompability. The emergence of exosome research has offered a better understanding of disease treatment and created novel opportunities for developing effective drug delivery systems with high biocompability. Moreover, RNA interference has emerged as a promising strategy for disease treatments by selectively knocking down or over-expressing specific genes, which allows new possibilities to directly control cell signaling events or drug resistance. Recently, more and more interests have been paid to develop optimal delivery nanosystems with high efficiency and high biocompability for drug and functional RNA co-delivery to achieve enhanced chemotherapy. In light of the challenges for developing drug and RNA co-delivery system, exosomes have been found to show very attractive prospects. This review aims to explore current technologies and challenges in the use of exosomes as drug and RNA co-delivery system with a focus on the emerging trends and issues associated with their further applications, which may contribute to the accelerated developments of exosome-based theraputics.
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Affiliation(s)
- Haorong Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Hanbo Yao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiaxin Chi
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Chaowei Li
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yilin Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiayi Yang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiaqi Yu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiajun Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Jun-Fa Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
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17
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Guo Y, Wang S, Liang F, Wang M. Identification of CHMP7 as a promising immunobiomarker for immunotherapy and chemotherapy and impact on prognosis of colorectal cancer patients. Front Cell Dev Biol 2023; 11:1211843. [PMID: 37711849 PMCID: PMC10499328 DOI: 10.3389/fcell.2023.1211843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/09/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction: ESCRT is a molecular machine involved in various important physiological processes, such as the formation of multivesicular bodies, cellular autophagy, and cellular membrane repair. CHMP7 is a regulatory subunit of ESCRT-III and is necessary for the proper functioning of ESCRT. In this study, public databases were exploited to explore the role of CHMP7 in tumors. Methods: The research on CHMP7 in oncology is rather limited. In this study, the differential expression of CHMP7 in multiple tumor tissues was analyzed with information from public databases and clinically collected colorectal cancer tissue samples. Subsequently, the mutational landscape of CHMP7, methylation levels, and the relationship between its expression levels and genomic instability were resolved. The immune microenvironment is a compelling emerging star in tumor research. The correlation of CHMP7 with various infiltrating immune cell types in TME was analyzed by online datasets and single-cell sequencing. In terms of clinical treatment, the impact of CHMP7 expression levels on chemotherapy and immunotherapy and the evaluation of small molecule drugs related to CHMP7 were assessed. Results: CHMP7 has a predictive value for the prognosis of patients with tumors and is highly involved in tumor immunity. The downregulation of CHMP7 may lead to genomic instability. A strong correlation between CHMP7 and TME immune cell infiltration has been observed, participating in the formation of suppressive TME and promoting tumor progression. The expression level of CHMP7 is significantly lower in the non-responder group of multiple chemotherapeutic agents. CHMP7 can potentially serve as a new biomarker for predicting the efficacy of tumor chemotherapy and immunotherapy. Conclusion: As a gene of interest, CHMP7 is expected to provide novel and promising targets for further treatment of patients with tumor.
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Affiliation(s)
- Yu Guo
- Department of the General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Shu Wang
- Department of the Ridiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Feng Liang
- Department of the General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Min Wang
- Department of the General Surgery, The Second Hospital of Jilin University, Changchun, China
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18
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Seay TW, Suo Z. Roles of Extracellular Vesicles on the Progression and Metastasis of Hepatocellular Carcinoma. Cells 2023; 12:1879. [PMID: 37508544 PMCID: PMC10378249 DOI: 10.3390/cells12141879] [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: 05/12/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
Liver cancer is a global health challenge as it is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is often found in liver cells, where it is associated with high morbidity and mortality rates. Recent studies have shown that extracellular vesicles (EVs) secreted by HCC cells play a critical role in HCC progression and metastasis. EVs contain proteins, nucleic acids, lipids, and metabolites as cargos. EVs derived from HCC cells can transfer oncogenic factors to surrounding cells leading to increased tumor growth, cell invasion, and angiogenesis. In this review, we summarize the roles that EVs play and the specific effects of their cargos on HCC progression and metastasis and identify potential therapeutic targets for HCC treatment.
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Affiliation(s)
- Turner W Seay
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Zucai Suo
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
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19
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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20
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Yao M, Liang S, Cheng B. Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine. Front Pharmacol 2023; 14:1110922. [PMID: 36733504 PMCID: PMC9886889 DOI: 10.3389/fphar.2023.1110922] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) usually occurs on the basis of chronic liver inflammatory diseases and cirrhosis. The liver microenvironment plays a vital role in the tumor initiation and progression. Exosomes, which are nanometer-sized membrane vesicles are secreted by a number of cell types. Exosomes carry multiple proteins, DNAs and various forms of RNA, and are mediators of cell-cell communication and regulate the tumor microenvironment. In the recent decade, many studies have demonstrated that exosomes are involved in the communication between HCC cells and the stromal cells, including endothelial cells, macrophages, hepatic stellate cells and the immune cells, and serve as a regulator in the tumor proliferation and metastasis, immune evasion and immunotherapy. In addition, exosomes can also be used for the diagnosis and treatment HCC. They can potentially serve as specific biomarkers for early diagnosis and drug delivery vehicles of HCC. Chinese herbal medicine, which is widely used in the prevention and treatment of HCC in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. In this review, we summarized the latest progresses on the role of the exosomes in the initiation, progression and treatment of HCC and the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.
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Affiliation(s)
- Man Yao
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China,Faculty of Traditional Chinese Medicine, Naval Medical University (The Second Military Medical University), Shanghai, China,*Correspondence: Binbin Cheng,
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21
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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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22
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Lu Z, Chen Y, Luo W, Ding L, Wang H, Li Y, Yang BW, Ren L, Zheng Q, Xie H, Wang R, Yu C, Lin Y, Zhou Z, Xia L, Li G. Exosomes in Genitourinary Cancers: Emerging Mediators of Drug Resistance and Promising Biomarkers. Int J Biol Sci 2023; 19:167-182. [PMID: 36594094 PMCID: PMC9760437 DOI: 10.7150/ijbs.78321] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/01/2022] [Indexed: 11/24/2022] Open
Abstract
Drug resistance presents a major obstacle in the treatment of genitourinary cancers. Exosomes as the medium of intercellular communication serve important biological functions and play essential roles in pathological processes, including drug response. Through the transfer of bioactive cargoes, exosomes can modulate drug resistance via multiple mechanisms. This review attempts to elucidate the mechanisms of exosomal cargoes with reference to tumor drug resistance, their role in genitourinary cancers, and their potential clinical applications as candidate biomarkers in liquid biopsy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Liqun Xia
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gonghui Li
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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23
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Nishiwada S, Cui Y, Sho M, Jun E, Akahori T, Nakamura K, Sonohara F, Yamada S, Fujii T, Han IW, Tsai S, Kodera Y, Park JO, Von Hoff D, Kim SC, Li W, Goel A. Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients With Pancreatic Ductal Adenocarcinoma. Ann Surg 2022; 276:e876-e885. [PMID: 34132691 PMCID: PMC8674379 DOI: 10.1097/sla.0000000000004993] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY OF BACKGROUND DATA Pretreatment risk stratification is essential for offering individualized treatments to patients with PDAC, but predicting recurrence following surgery remains clinically challenging. METHODS We analyzed 210 plasma and serum specimens from 4 cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence [area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.70-0.89] and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65- 0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (hazard ratio: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS We identified a novel, noninvasive exo-miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.
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Affiliation(s)
- Satoshi Nishiwada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Department of Surgery, Nara Medical University, Nara, Japan
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Ya Cui
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Nara, Japan
| | - Eunsung Jun
- Department of Convergence Medicine and Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Institute for Life Sciences, AMIST, Asan Medical Center, Seoul, Korea
| | | | - Kota Nakamura
- Department of Surgery, Nara Medical University, Nara, Japan
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - In Woong Han
- Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Susan Tsai
- Pancreatic Cancer Program, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Song Cheol Kim
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Biomedical Engineering Research Center, AMIST, Asan Medical Center, Seoul, Korea
| | - Wei Li
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
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24
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Mahmoudvand S, Shokri S, Nakhaie M, Jalilian FA, Mehri-Ghahfarrokhi A, Yarani R, Shojaeian A. Small extracellular vesicles as key players in cancer development caused by human oncogenic viruses. Infect Agent Cancer 2022; 17:58. [DOI: 10.1186/s13027-022-00471-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022] Open
Abstract
Abstract
Background
Exosomes are the smallest group of extracellular vesicles in size from 30 to 150 nm, surrounded by a lipid bilayer membrane, and originate from multivesicular bodies secreted by different types of cells, such as virus-infected cells. The critical role of exosomes is information transfer among cells, representing a unique way for intercellular communication via a load of many kinds of molecules, including various signaling proteins and nucleic acids. In this review, we aimed to comprehensively investigate the role of exosomes in promoting human oncogenic viruses-associated cancers.
Methods
Our search was conducted for published researches between 2000 and 2022 by using several international databases includeing Scopus, PubMed, and Web of Science as well as Google scholar. We also reviewed additional evidence from relevant published articles.
Results
It has been shown that exosomes can create the conditions for viral spread in viral infections. Exosome secretion in a human tumor virus can switch on the cell signaling pathways by transferring exosome-encapsulated molecules, including viral oncoproteins, signal transduction molecules, and virus-encoded miRNAs, into various cells.
Conclusion
Given the role of exosomes in viruses-associated cancers, they can also be considered as molecular targets in diagnosis and treatment.
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25
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Yeung CLS, Yam JWP. Therapy-induced modulation of extracellular vesicles in hepatocellular carcinoma. Semin Cancer Biol 2022; 86:1088-1101. [PMID: 35158067 DOI: 10.1016/j.semcancer.2022.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 01/27/2023]
Abstract
Despite rapid development of anti-tumorigenic treatments, the clinical outcome for hepatocellular carcinoma (HCC) is still far from satisfactory. With a deeper understanding about tumor microenvironment (TME), the critical role of extracellular vesicles (EVs) as intercellular liaison has come into spotlight. The dynamic functionality of these nanoparticles revealed cancer cells can employ both tumor and non-tumorous components for their own benefit, so as to mediate cell-to-cell communication and interchange of oncogenic biomolecules. Increasing studies on HCC-derived EVs have identified various irregulated biomolecules, that may serve as biomarkers or therapeutic targets. In this review, we first introduce the current knowledge about EVs and how they operate to maintain a healthy liver microenvironment. We then summarize some of the aberrant observations reported on HCC-derived EVs and how they contribute to HCC pathogenesis. Finally, we describe how current treatments for HCC alter behavior of EVs, which may shed light for potential prognostic markers and therapeutic strategies.
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Affiliation(s)
- Cherlie Lot Sum Yeung
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research (The University of Hong Kong), Hong Kong.
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26
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Huang H, Zhang Q, Zhang Y, Sun X, Liu C, Wang Q, Huang Y, Li Q, Wu Z, Pu C, Sun A. Identification of the Level of Exosomal Protein by Parallel Reaction Monitoring Technology in HCC Patients. Int J Gen Med 2022; 15:7831-7842. [PMID: 36267426 PMCID: PMC9578473 DOI: 10.2147/ijgm.s384140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/05/2022] [Indexed: 12/02/2022] Open
Abstract
PURPOSE Reliable biomarkers for the diagnosis and differential diagnosis of various stages of liver cancer are lacking. In this study, we aim to detect the levels of differentially expressed proteins (DEPs) in serum exosomes of patients with different liver diseases using a sensitive method. PATIENTS AND METHODS Exosomes were purified and validated. The expression of DEPs in exosomes from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) was validated by parallel reaction monitoring (PRM) technology and Western blotting, and the biological functions were analyzed by bioinformatics analysis. RESULTS A total of 11 DEPs were identified by PRM technology. Significantly higher level of haptoglobin (Hp) was detected in HCC patients as compared to LC and CHB patients. HCC patients had a significantly lower level of transthyretin (TTR) in the patients with CHB. Among the patients with HCC who undertaken surgery, the postoperative levels of CRP, SERPINA3 and Heparin cofactor 2 (SERPIND1) were significantly reduced compared to their respective preoperative levels. CONCLUSION Hp and TTR may be potential markers for early diagnosis of HCC. CRP, SERPINA3 and SERPIND1 may serve as potential prognostic indicators for HCC patients undertaken surgery.
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Affiliation(s)
- Hui Huang
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Qiqi Zhang
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Yong Zhang
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Xueying Sun
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Chunyan Liu
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Qi Wang
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Yushuang Huang
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China
| | - Qingwei Li
- College of Life Science, Liaoning Normal University, Dalian, 116081, People’s Republic of China
| | - Zepan Wu
- College of Life Science, Liaoning Normal University, Dalian, 116081, People’s Republic of China
| | - Chunwen Pu
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China,Correspondence: Chunwen Pu, Department of Biobank, Dalian Public Health Clinical Center, No. 269, Guibai Road, Ganjingzi District, Dalian, 116001, People’s Republic of China, Email
| | - Aijun Sun
- Department of Biobank, Dalian Public Health Clinical Center, Dalian, 116001, People’s Republic of China,Aijun Sun, Department of biobank, Dalian Public Health Clinical Center, No. 269, Guibai Road, Ganjingzi District, Dalian, 116001, People’s Republic of China, Email
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27
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Gerloff D, Kewitz-Hempel S, Hause G, Ehrenreich J, Golle L, Kingreen T, Sunderkötter C. Comprehensive Analyses of miRNAs Revealed miR-92b-3p, miR-182-5p and miR-183-5p as Potential Novel Biomarkers in Melanoma-Derived Extracellular Vesicles. Front Oncol 2022; 12:935816. [PMID: 35898875 PMCID: PMC9309285 DOI: 10.3389/fonc.2022.935816] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/16/2022] [Indexed: 11/20/2022] Open
Abstract
Extracellular vesicles (EVs) are important mediators in the intercellular communication, influencing the function and phenotype of different cell types within the tumor micro-milieu and thus promote tumor progression. Since EVs safely transport packages of proteins, lipids and also nucleic acids such as miRNAs, EVs and their cargo can serve as diagnostic and prognostic markers. Therefore, the aim of this study was to investigate EV embedded miRNAs specific for melanoma, which could serve as potential biomarkers. In contrast to previous studies, we not only analysed miRNAs from EVs, but also included the miRNA profiles from the EV-secreting cells to identify candidates as suitable biomarkers. While the characterization of EVs derived from normal melanocytes and melanoma cells showed largely comparable properties with regard to size distribution and expression of protein markers, the NGS analyses yielded marked differences for several miRNAs. While miRNA load of EVs derived from normal human epidermal melanocytes (NHEMs) and melanoma cells were very similar, they were highly different from their secreting cells. By comprehensive analyses, six miRNAs were identified to be enriched in both melanoma cells and melanoma cell-derived EVs. Of those, the accumulation of miR-92b-3p, miR-182-5p and miR-183-5p in EVs could be validated in vitro. By functional network generation and pathway enrichment analysis we revealed an association with different tumor entities and signaling pathways contributing melanoma progression. Furthermore, we found that miR-92b-3p, miR-182-5p and miR-183-5p were also enriched in EVs derived from serum of melanoma patients. Our results support the hypothesis that miRNAs derived from EVs can serve as prognostic or diagnostic liquid biopsy markers in melanoma. We identified EV-derived miRNAs and showed that those miRNAs, which were enriched in melanoma cells and EVs, are also found elevated in serum-derived EVs of patients with metastatic melanoma, but not in healthy subjects.
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Affiliation(s)
- Dennis Gerloff
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
- *Correspondence: Dennis Gerloff,
| | - Stefanie Kewitz-Hempel
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Gerd Hause
- Biocenter, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Jovine Ehrenreich
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Linda Golle
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Tim Kingreen
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Cord Sunderkötter
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
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28
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Aguirre RS, Kulkarni A, Becker MW, Lei X, Sarkar S, Ramanadham S, Phelps EA, Nakayasu ES, Sims EK, Mirmira RG. Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling. Mol Metab 2022; 63:101545. [PMID: 35817393 PMCID: PMC9294332 DOI: 10.1016/j.molmet.2022.101545] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/03/2022] [Accepted: 07/05/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between β cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been seen as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by β cells constitute an additional and biologically important mechanism for transmitting signals to within the islet. SCOPE OF REVIEW This review summarizes the general mechanisms of EV formation, with a particular focus on how lipids and lipid signaling pathways influence their formation and cargo. We review the implications of EV release from β cells for T1D pathogenesis, how EVs and their cargo might be leveraged as biomarkers of this process, and how EVs might be engineered as a therapeutic candidate to counter T1D outcomes. MAJOR CONCLUSIONS Islet β cells have been viewed as initiators and propagators of the cellular circuit giving rise to autoimmunity in T1D. In this context, emerging literature suggests that EVs may represent a conduit for communication that holds more comprehensive messaging about the β cells from which they arise. As the field of EV biology advances, it opens the possibility that intervening with EV formation and cargo loading could be a novel disease-modifying approach in T1D.
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Affiliation(s)
| | - Abhishek Kulkarni
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA
| | - Matthew W. Becker
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Xiaoyong Lei
- Department of Cell, Developmental, and Integrative Biology & The Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Soumyadeep Sarkar
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Sasanka Ramanadham
- Department of Cell, Developmental, and Integrative Biology & The Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Edward A. Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Ernesto S. Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Emily K. Sims
- Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Raghavendra G. Mirmira
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA,Corresponding author. 900 E. 57th St., KCBD 8130, Chicago, IL, 60637, USA.
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29
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Wang H, Yu L, Huang P, Zhou Y, Zheng W, Meng N, He R, Xu Y, Keong TS, Cui Y. Tumor-associated Exosomes Are Involved in Hepatocellular Carcinoma Tumorigenesis, Diagnosis, and Treatment. J Clin Transl Hepatol 2022; 10:496-508. [PMID: 35836772 PMCID: PMC9240252 DOI: 10.14218/jcth.2021.00425] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/17/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has become a challenging disease worldwide. There are still limitations in the diagnosis and treatment of HCC, and its high metastatic capacity and high recurrence rate are the main reasons for its poor prognosis. The ability of extracellular vesicles (EVs) to transfer functionally-active substances and their widespread presence in almost all body fluids suggest their unprecedented potential in the study of various cancers. The unique physicochemical properties of EVs determine their potential as antitumor vaccines and drug carriers. In the last decade, the study of EVs in HCC has evolved from a single hot topic to a system with considerable scale. This paper summarizes the role of EVs, especially exosomes, in the occurrence, metastasis and tumor immunity of HCC, reviews their applications in tumor diagnosis, prognosis and treatment, describes the pros and cons of these studies, and looks forward towards the future research directions of EVs in HCC.
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Affiliation(s)
- Hang Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Liang Yu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Peng Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Yongxu Zhou
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Wangyang Zheng
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Nanfeng Meng
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Correspondence to: Yunfu Cui and Yi Xu, Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, Heilongjiang 150086, China. ORCID: https://orcid.org/0000-0001-7393-1680 (YC), https://orcid.org/0000-0003-2720-0005 (YX). Tel: +86-451-86605113, Fax: +86-451-86605356, E-mail: (YC) or (YX); Tey Sze Keong, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: +852-22552706, Fax: +852-28725197, E-mail:
| | - Tey Sze Keong
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Correspondence to: Yunfu Cui and Yi Xu, Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, Heilongjiang 150086, China. ORCID: https://orcid.org/0000-0001-7393-1680 (YC), https://orcid.org/0000-0003-2720-0005 (YX). Tel: +86-451-86605113, Fax: +86-451-86605356, E-mail: (YC) or (YX); Tey Sze Keong, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: +852-22552706, Fax: +852-28725197, E-mail:
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Correspondence to: Yunfu Cui and Yi Xu, Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, Heilongjiang 150086, China. ORCID: https://orcid.org/0000-0001-7393-1680 (YC), https://orcid.org/0000-0003-2720-0005 (YX). Tel: +86-451-86605113, Fax: +86-451-86605356, E-mail: (YC) or (YX); Tey Sze Keong, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: +852-22552706, Fax: +852-28725197, E-mail:
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30
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Wang J, Wang X, Zhang X, Shao T, Luo Y, Wang W, Han Y. Extracellular Vesicles and Hepatocellular Carcinoma: Opportunities and Challenges. Front Oncol 2022; 12:884369. [PMID: 35692794 PMCID: PMC9175035 DOI: 10.3389/fonc.2022.884369] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/25/2022] [Indexed: 12/05/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. Extracellular vesicles (EVs) contain sufficient bioactive substances and are carriers of intercellular information exchange, as well as delivery vehicles for nucleic acids, proteins and drugs. Although EVs show great potential for the treatment of HCC and their role in HCC progression has been extensively studied, there are still many challenges such as time-consuming extraction, difficult storage, easy contamination, and low drug loading rate. We focus on the biogenesis, morphological characteristics, isolation and extraction of EVs and their significance in the progression of HCC, tumor invasion, immune escape and cancer therapy for a review. EVs may be effective biomarkers for molecular diagnosis of HCC and new targets for tumor-targeted therapy.
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Affiliation(s)
- Juan Wang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoya Wang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Xintong Zhang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Tingting Shao
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yanmei Luo
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Wei Wang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yunwei Han
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Academician (Expert) Workstation of Sichuan Province, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China.,School of Basic Medical Sciences, Shandong University, Jinan, China
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31
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Badami E, Busà R, Douradinha B, Russelli G, Miceli V, Gallo A, Zito G, Conaldi PG, Iannolo G. Hepatocellular carcinoma, hepatitis C virus infection and miRNA involvement: Perspectives for new therapeutic approaches. World J Gastroenterol 2022; 28:2417-2428. [PMID: 35979260 PMCID: PMC9258280 DOI: 10.3748/wjg.v28.i22.2417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/22/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the principal etiology of cirrhosis and, ultimately, hepatocellular carcinoma (HCC). At present, approximately 71 million people are chronically infected with HCV, and 10%-20% of these are expected to develop severe liver complications throughout their lifetime. Scientific evidence has clearly shown the causal association between miRNAs, HCV infection and HCC. Although it is not completely clear whether miRNA dysregulation in HCC is the cause or the consequence of its development, variations in miRNA patterns have been described in different liver diseases, including HCC. Many studies have analyzed the importance of circulating miRNAs and their effect on cell proliferation and apoptosis. In this Review, we aim to summarize current knowledge on the association between miRNA, HCV and HCC from a diagnostic point of view, and also the potential implications for therapeutic approaches.
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Affiliation(s)
- Ester Badami
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Bruno Douradinha
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Giovanna Russelli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Vitale Miceli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Giovanni Zito
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
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32
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Qin W, Wang L, Tian H, Wu X, Xiao C, Pan Y, Fan M, Tai Y, Liu W, Zhang Q, Yang Y. CAF-derived exosomes transmitted Gremlin-1 promotes cancer progression and decreases the sensitivity of hepatoma cells to sorafenib. Mol Carcinog 2022; 61:764-775. [PMID: 35638711 DOI: 10.1002/mc.23416] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/29/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide because of metastasis. An increasing number of studies have reported that cancer-associated fibroblasts (CAFs) have emerged as the largest component of the stroma and play a critical role in tumor-promoting processes. However, the effects of CAFs on cancer progression and the sensitivity of hepatoma cells to sorafenib are not well characterized. Here, we identified the proteome of CAF-derived exosomes, and unveiled that exosomal Gremlin-1 derived from CAFs contributes to epithelial-mesenchymal transition (EMT) of hepatoma cells and the decrease of the sorafenib sensitivity through regulating Wnt/β-catenin and BMP signaling pathways. Compared to control subjects, the level of plasma exosomal Gremlin-1 was significantly increased in HCC patients. Further studies indicated that plasma exosomal Gremlin-1 may predict sorafenib response in HCC patients. Collectively, our findings uncover CAFs-derived Gremlin-1-rich exosomes promote EMT and decrease the sensitivity of hepatoma cells to sorafenib by Wnt/β-catenin and BMP signaling.
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Affiliation(s)
- Wei Qin
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Wang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huan Tian
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaocai Wu
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Cuicui Xiao
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuhang Pan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingming Fan
- Department of Surgery Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Tai
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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33
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Tang J, He J, Feng C, Tu C. Exosomal MiRNAs in Osteosarcoma: Biogenesis and Biological Functions. Front Pharmacol 2022; 13:902049. [PMID: 35592419 PMCID: PMC9110813 DOI: 10.3389/fphar.2022.902049] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/19/2022] [Indexed: 12/05/2022] Open
Abstract
MiRNAs are a group of non-coding RNA molecules that function in mRNA translational inhibition via base-pairing with complementary sequences in target mRNA. In oncology, miRNAs have raised great attention due to their aberrant expression and pivotal roles in the pathogenesis of multiple malignancies including osteosarcoma. MiRNAs can be transported by exosome, the nano-extracellular vesicle with a diameter of 30–150 nm. Recently, a growing number of studies have demonstrated that exosomal miRNAs play a critical role in tumor initiation and progression, by exerting multiple biological functions including metastasis, angiogenesis, drug resistance and immunosuppression. In this review, we aim to depict the biogenesis of exosomal miRNAs and summarize the potential diagnostic and therapeutic functions of exosomal miRNAs in osteosarcoma.
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Affiliation(s)
- Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Jieyu He
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chengyao Feng
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
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34
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Bakhsh T, Alhazmi S, Alburae NA, Farsi A, Alzahrani F, Choudhry H, Bahieldin A. Exosomal miRNAs as a Promising Source of Biomarkers in Colorectal Cancer Progression. Int J Mol Sci 2022; 23:ijms23094855. [PMID: 35563246 PMCID: PMC9103063 DOI: 10.3390/ijms23094855] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer worldwide amongst males and females. CRC treatment is multidisciplinary, often including surgery, chemotherapy, and radiotherapy. Early diagnosis of CRC can lead to treatment initiation at an earlier stage. Blood biomarkers are currently used to detect CRC, but because of their low sensitivity and specificity, they are considered inadequate diagnostic tools and are used mainly for following up patients for recurrence. It is necessary to detect novel, noninvasive, specific, and sensitive biomarkers for the screening and diagnosis of CRC at earlier stages. The tumor microenvironment (TME) has an essential role in tumorigenesis; for example, extracellular vesicles (EVs) such as exosomes can play a crucial role in communication between cancer cells and different components of TME, thereby inducing tumor progression. The importance of miRNAs that are sorted into exosomes has recently attracted scientists’ attention. Some unique sequences of miRNAs are favorably packaged into exosomes, and it has been illustrated that particular miRNAs can be directed into exosomes by special mechanisms that occur inside the cells. This review illustrates and discusses the sorted and transported exosomal miRNAs in the CRC microenvironment and their impact on CRC progression as well as their potential use as biomarkers.
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Affiliation(s)
- Tahani Bakhsh
- Department of Biology, Faculty of Science, Jeddah University, Jeddah 21589, Saudi Arabia
- Correspondence:
| | - Safiah Alhazmi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
| | - Najla Ali Alburae
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
| | - Ali Farsi
- Department of Surgry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Faisal Alzahrani
- King Fahd Medical Research Center, Embryonic Stem Cells Unit, Department of Biochemistry, Faculty of Science, King AbdulAziz University, Jeddah 21589, Saudi Arabia;
- Centre of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Hani Choudhry
- Centre of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ahmed Bahieldin
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
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35
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Wang BZ, Luo L, Vunjak-Novakovic G. RNA and Protein Delivery by Cell-Secreted and Bioengineered Extracellular Vesicles. Adv Healthc Mater 2022; 11:e2101557. [PMID: 34706168 PMCID: PMC8891029 DOI: 10.1002/adhm.202101557] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/28/2021] [Indexed: 12/22/2022]
Abstract
Extracellular vesicles (EVs) are carriers of biological signals through export and delivery of RNAs and proteins. Of increasing interest is the use of EVs as a platform for delivery of biomolecules. Preclinical studies have effectively used EVs to treat a number of diseases. Uniquely, endogenous machinery within cells can be manipulated in order to produce desirable loading of cargo within secreted EVs. In order to inform the development of such approaches, an understanding of the cellular mechanisms by which cargo is sorted to EVs is required. Here, the current knowledge of cargo sorting within EVs is reviewed. Here is given an overview of recent bioengineering approaches that leverage these advances. Methods of externally manipulating EV cargo are also discussed. Finally, a perspective on the current challenges of EVs as a drug delivery platform is offered. It is proposed that standardized bioengineering methods for therapeutic EV preparation will be required to create a well-defined clinical product.
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Affiliation(s)
- Bryan Z. Wang
- Department of Biomedical Engineering, 622 West 168th Street VC12-234, 10032, U.S.A
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
| | - Lori Luo
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, 622 West 168th Street VC12-234, 10032, U.S.A
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
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36
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Li S, Chen L. Exosomes in Pathogenesis, Diagnosis, and Treatment of Hepatocellular Carcinoma. Front Oncol 2022; 12:793432. [PMID: 35155236 PMCID: PMC8828506 DOI: 10.3389/fonc.2022.793432] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes are extracellular vesicles with a diameter of 30-150 nm that are released by most types of cells and have been confirmed to be involved in many physical and pathological processes, especially in cell to cell communication. Compared with other vesicles, exosomes have a unique double-layer saclike structure that allows them to be present stably in various body fluids, including blood, cerebrospinal fluid, urine, saliva, and serous cavity effusion. The cargoes of exosomes reflect the characteristics of host cells. Due to the nature of hepatocellular carcinoma (HCC) cells, heterogeneity in the bioactive substances usually exist in exosomes. In addition, exosomes can efficiently deliver cargoes to the target cells to exert pathological functions, playing important role in tumor occurrence, development, metastasis, immune regulation, and drug resistance. Previous studies have been shown that exosomes have wide applications in diagnosis and treatment of HCC. In this review, we discuss these recent findings and highlight the significant roles of exosomes in HCC, focusing on the effect and underlying mechanisms of exosomes to regulate HCC progression and the potential clinical value of exosomes as biomarkers and therapeutic targets.
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Affiliation(s)
- Shuang Li
- Institute of Basic Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Provincial Key Laboratory for Transfusion-Transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
| | - Limin Chen
- Provincial Key Laboratory for Transfusion-Transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.,The Joint Laboratory on Transfusion-Transmitted Diseases (TTD) Between Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Nanning Blood Center, Nanning Blood Center, Nanning, China
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37
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Babuta M, Szabo G. Extracellular vesicles in inflammation: Focus on the microRNA cargo of EVs in modulation of liver diseases. J Leukoc Biol 2022; 111:75-92. [PMID: 34755380 PMCID: PMC9235439 DOI: 10.1002/jlb.3mir0321-156r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous nanometer-ranged particles that are released by cells under both normal and pathological conditions. EV cargo comprises of DNA, protein, lipids cargo, metabolites, mRNA, and non-coding RNA that can modulate the immune system by altering inflammatory response. EV associated miRNAs contribute to the pathobiology of alcoholic liver disease, non-alcoholic liver disease, viral hepatitis, acetaminophen-induced liver injury, fibrosis, and hepatocellular carcinoma. In context of liver diseases, EVs, via their cargo, alter the inflammatory response by communicating with different cell types within the liver and between liver and other organs. Here, the role of EVs and its associated miRNA in inter-cellular communication in different liver disease and as a potential biomarker and therapeutic target is reviewed.
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Affiliation(s)
- Mrigya Babuta
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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38
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Li Y, Wu J, Liu R, Zhang Y, Li X. Extracellular vesicles: catching the light of intercellular communication in fibrotic liver diseases. Theranostics 2022; 12:6955-6971. [PMID: 36276639 PMCID: PMC9576620 DOI: 10.7150/thno.77256] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/20/2022] [Indexed: 02/05/2023] Open
Abstract
The increasing prevalence of fibrotic liver diseases resulting from different etiologies has become a major global problem for public health. Fibrotic liver diseases represent a redundant accumulation of extracellular matrix, dysregulation of immune homeostasis and angiogenesis, which eventually contribute to the progression of cirrhosis and liver malignancies. The concerted actions among liver cells including hepatocytes, hepatic stellate cells, kupffer cells, liver sinusoidal endothelial cells and other immune cells are essential for the outcome of liver fibrosis. Recently, a growing body of literature has highlighted that extracellular vesicles (EVs) are critical mediators of intercellular communication among different liver cells either in local or distant microenvironments, coordinating a variety of systemic pathological and physiological processes. Despite the increasing interests in this field, there are still relatively few studies to classify the contents and functions of EVs in intercellular transmission during hepatic fibrogenesis. This review aims to summarize the latest findings with regards to the cargo loading, release, and uptake of EVs in different liver cells and clarify the significant roles of EVs played in fibrotic liver diseases.
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Affiliation(s)
- Yijie Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jianzhi Wu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yinhao Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
- ✉ Corresponding author: Xiaojiaoyang Li, Ph.D., School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. E-mail:
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39
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Zhou H, Yan ZH, Yuan Y, Xing C, Jiang N. The Role of Exosomes in Viral Hepatitis and Its Associated Liver Diseases. Front Med (Lausanne) 2021; 8:782485. [PMID: 34881274 PMCID: PMC8645545 DOI: 10.3389/fmed.2021.782485] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
Exosomes, the important carriers between cells, can carry proteins, micro ribonucleic acids (miRNAs), long non-coding RNAs (lncRNAs) and other molecules to mediate cellular information transduction. They also play an important role in the pathogenesis, prognosis and treatment of viral hepatitis and its associated liver diseases. Several studies have reported that viral hepatitis and its associated liver diseases, including hepatitis A, B, C and E; hepatic fibrosis and hepatocellular carcinoma, were closely associated with exosomes. Exploring the role of exosomes in viral hepatitis and associated liver diseases will enhance our understanding of these diseases. Therefore, this review mainly summarised the role of exosomes in viral hepatitis and its associated liver diseases to identify new strategies for liver diseases in clinical practise.
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Affiliation(s)
- Hao Zhou
- Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi-Han Yan
- Department of Hepatology, Wuxi Fifth People's Hospital, Wuxi, China
| | - Yuan Yuan
- Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chen Xing
- Department of Oncology, The Second People's Hospital of Yancheng City, Yancheng, China
| | - Nan Jiang
- Department of Urology, People's Hospital of Dongtai City, Dongtai, China
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40
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Guan XY, Guan XL, Jiao ZY. Improving therapeutic resistance: beginning with targeting the tumor microenvironment. J Chemother 2021; 34:492-516. [PMID: 34873999 DOI: 10.1080/1120009x.2021.2011661] [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: 10/19/2022]
Abstract
Cancer is a serious threat to human health and life. The tumor microenvironment (TME) not only plays a key role in the occurrence, development and metastasis of cancer, but also has a profound impact on treatment resistance. To improve and solve this problem, an increasing number of strategies targeting the TME have been proposed, and great progress has been made in recent years. This article reviews the characteristics and functions of the main matrix components of the TME and the mechanisms by which each component affects drug resistance. Furthermore, this article elaborates on targeting the TME as a strategy to treat acquired drug resistance, reduce tumor metastasis, recurrence, and improve efficacy.
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Affiliation(s)
- Xiao-Ying Guan
- Pathology Department, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xiao-Li Guan
- General Medicine Department, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zuo-Yi Jiao
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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41
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Zhu X, Yang H, Zhang M, Wu X, Jiang L, Liu X, Lv K. YTHDC1-mediated VPS25 regulates cell cycle by targeting JAK-STAT signaling in human glioma cells. Cancer Cell Int 2021; 21:645. [PMID: 34863175 PMCID: PMC8642909 DOI: 10.1186/s12935-021-02304-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Glioma is a common type of malignant brain tumor with a high mortality and relapse rate. The endosomal sorting complex required for transport (ESCRT) has been reported to be involved in tumorigenesis. However, the molecular mechanisms have not been clarified. METHODS Bioinformatics was used to screen the ESCRT subunits highly expressed in glioma tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The function of the ESCRT subunits in glioma cells was examined in vitro. Transcriptome sequencing analyzed the target genes and signaling pathways affected by the ESCRT subunit. Finally, the relationship between m6A (N6-methyladenosine) modification and high expression of the ESCRT subunit was studied. RESULTS VPS25 was upregulated in glioma tissues, which was correlated with poor prognosis in glioma patients. Furthermore, VPS25 knockdown inhibited the proliferation, blocked the cell cycle, and promoted apoptosis in glioma cells. Meanwhile, VPS25 induced a G0/G1 phase arrest of the cell cycle in glioma cells by directly mediating p21, CDK2, and cyclin E expression, and JAK-signal transducer and activator of transcription (STAT) activation. Finally, YTHDC1 inhibited glioma proliferation by reducing the expression of VPS25. CONCLUSION These results suggest that VPS25 is a promising prognostic indicator and a potential therapeutic target for glioma.
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Affiliation(s)
- Xiaolong Zhu
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China.,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China.,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China
| | - Hui Yang
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China.,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China.,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China
| | - Mengying Zhang
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China.,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China.,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China
| | - Xingwei Wu
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China.,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China.,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China
| | - Lan Jiang
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China.,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China.,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China
| | - Xiaocen Liu
- Department of Nuclear Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, People's Republic of China
| | - Kun Lv
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China. .,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes (Wannan Medical College), Wuhu, 241001, People's Republic of China. .,Non-Coding RNA Research Center of Wannan Medical College, Wuhu, 241001, China.
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Nimitrungtawee N, Inmutto N, Chattipakorn SC, Chattipakorn N. Extracellular vesicles as a new hope for diagnosis and therapeutic intervention for hepatocellular carcinoma. Cancer Med 2021; 10:8253-8271. [PMID: 34708589 PMCID: PMC8633266 DOI: 10.1002/cam4.4370] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/09/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer with a high mortality rate. Early diagnosis and treatment before tumor progression into an advanced stage is ideal. The current diagnosis of HCC is mainly based on imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging. These methods have some limitations including diagnosis in the case of very small tumors with atypical imaging patterns. Extracellular vesicles (EVs) are nanosized vesicles which have been shown to act as an important vector for cell-to-cell communication. In the past decade, EVs have been investigated with regard to their roles in HCC formation. Since these EVs contain biomolecular cargo such as nucleic acid, lipids, and proteins, it has been proposed that they could be a potential source of tumor biomarkers and a vector for therapeutic cargo. In this review, reports on the roles of HCC-derived EVs in tumorigenesis, and clinical investigations using circulating EVs as a biomarker for HCC and their potential diagnostic roles have been comprehensively summarized and discussed. In addition, findings from in vitro and in vivo reports investigating the potential roles of EVs as therapeutic interventions are also presented. These findings regarding the potential benefits of EVs will encourage further investigations and may allow us to devise novel strategies using EVs in the early diagnosis as well as for treatment of HCC in the future.
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Affiliation(s)
- Natthaphong Nimitrungtawee
- Diagnostic Radiology UnitDepartment of RadiologyFaculty of MedicineChiang Mai UniversityChiang MaiThailand
| | - Nakarin Inmutto
- Diagnostic Radiology UnitDepartment of RadiologyFaculty of MedicineChiang Mai UniversityChiang MaiThailand
| | - Siriporn C. Chattipakorn
- Cardiac Electrophysiology Research and Training CenterFaculty of MedicineChiang Mai UniversityChiang MaiThailand
- Cardiac Electrophysiology UnitDepartment of PhysiologyFaculty of MedicineChiang Mai UniversityChiang MaiThailand
- Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai UniversityChiang MaiThailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training CenterFaculty of MedicineChiang Mai UniversityChiang MaiThailand
- Cardiac Electrophysiology UnitDepartment of PhysiologyFaculty of MedicineChiang Mai UniversityChiang MaiThailand
- Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai UniversityChiang MaiThailand
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43
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Xu JL, Xu WX, Tang JH. Exosomal circRNAs: a new communication method in cancer. Am J Transl Res 2021; 13:12913-12928. [PMID: 34956507 PMCID: PMC8661201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/13/2021] [Indexed: 06/14/2023]
Abstract
Exosomes are extracellular vesicles with unique membrane markers and components that participate in cellular communication. The contents of exosomes, including growth factors, microRNAs, long noncoding RNAs, and circular RNAs (circRNAs), have been recognized as prognostic biomarkers and promote cancer progression through cancer cell growth, metastasis, angiogenesis, and cancer development. One of the components of exosomes, circRNAs, are covalently closed and prevented from degrading, which results in their continually accumulating in exosomes. Evidence suggests that exosomal circRNAs are abundant and stable in body fluids and have been implicated in many diseases. In this article we summarize the biogenesis and function of circRNAs and explore the expressions of exosomal circRNAs in cancer, emphasizing the fact that exosomal circRNAs are a novel diagnostic biomarker in the early stages of cancer and/or a therapeutic target in further cancer treatment.
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Affiliation(s)
- Jia-Lin Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Wen-Xiu Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Jin-Hai Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
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44
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Gu WJ, Shen YW, Zhang LJ, Zhang H, Nagle DG, Luan X, Liu SH. The multifaceted involvement of exosomes in tumor progression: Induction and inhibition. MedComm (Beijing) 2021; 2:297-314. [PMID: 34766148 PMCID: PMC8554660 DOI: 10.1002/mco2.49] [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: 08/24/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
As key performers in intercellular communication, exosomes released by tumor cells play an important role in cancer development, including angiogenesis, cancer‐associated fibroblasts activation, epithelial‐mesenchymal transformation (EMT), immune escape, and pre‐metastatic niche formation. Meanwhile, other cells in tumor microenvironment (TME) can secrete exosomes and facilitate tumor progression. Elucidating mechanisms regarding these processes may offer perspectives for exosome‐based antitumor strategies. In this review, we mainly introduce the versatile roles of tumor or stromal cell derived exosomes in cancer development, with a particular focus on the biological capabilities and functionalities of their diverse contents, such as miRNAs, lncRNAs, and circRNAs. The potential clinical application of exosomes as biomarkers in cancer diagnosis and prognosis is also discussed. Finally, the current antitumor strategies based on exosomes in immunotherapy and targeted delivery for chemotherapeutic or biological agents are summarized.
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Affiliation(s)
- Wen-Jie Gu
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
| | - Yi-Wen Shen
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
| | - Li-Jun Zhang
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
| | - Hong Zhang
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
| | - Dale G Nagle
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China.,Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences School of Pharmacy University of Mississippi University Mississippi USA
| | - Xin Luan
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
| | - San-Hong Liu
- Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China
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45
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Anakor E, Le Gall L, Dumonceaux J, Duddy WJ, Duguez S. Exosomes in Ageing and Motor Neurone Disease: Biogenesis, Uptake Mechanisms, Modifications in Disease and Uses in the Development of Biomarkers and Therapeutics. Cells 2021; 10:2930. [PMID: 34831153 PMCID: PMC8616058 DOI: 10.3390/cells10112930] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer's or Parkinson's disease, exosomes are suspected to propagate toxic proteins. The topic of this review is the role of exosomes in ageing conditions and more specifically in ALS. Our current understanding of exosomes and exosome-related mechanisms is first summarized in a general sense, including their biogenesis and secretion, heterogeneity, cellular interaction and intracellular fate. Their role in the Central Nervous System (CNS) and ageing of the neuromotor system is then considered in the context of exosome-induced signaling. The review then focuses on exosomes in age-associated neurodegenerative disease. The role of exosomes in ALS is highlighted, and their use as potential biomarkers to diagnose and prognose ALS is presented. The therapeutic implications of exosomes for ALS are considered, whether as delivery vehicles, neurotoxic targets or as corrective drugs in and of themselves. A diverse set of mechanisms underpin the functional roles, both confirmed and potential, of exosomes, generally in ageing and specifically in motor neurone disease. Aspects of their contents, biogenesis, uptake and modifications offer many plausible routes towards the development of novel biomarkers and therapeutics.
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Affiliation(s)
- Ekene Anakor
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47 6SB, UK; (E.A.); (L.L.G.); (J.D.); (W.J.D.)
| | - Laura Le Gall
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47 6SB, UK; (E.A.); (L.L.G.); (J.D.); (W.J.D.)
- NIHR Biomedical Research Centre, Great Ormond Street Institute of Child Health, Great Ormond Street Hospital NHS Trust, University College London, London WC1N 1EH, UK
| | - Julie Dumonceaux
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47 6SB, UK; (E.A.); (L.L.G.); (J.D.); (W.J.D.)
- NIHR Biomedical Research Centre, Great Ormond Street Institute of Child Health, Great Ormond Street Hospital NHS Trust, University College London, London WC1N 1EH, UK
| | - William John Duddy
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47 6SB, UK; (E.A.); (L.L.G.); (J.D.); (W.J.D.)
| | - Stephanie Duguez
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47 6SB, UK; (E.A.); (L.L.G.); (J.D.); (W.J.D.)
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Deng Y, Cao Y, Wang L, Ye D. The Role and Application of Salivary Exosomes in Malignant Neoplasms. Cancer Manag Res 2021; 13:5813-5820. [PMID: 34326665 PMCID: PMC8314680 DOI: 10.2147/cmar.s321225] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/10/2021] [Indexed: 11/23/2022] Open
Abstract
The study of salivary exosomes in malignant neoplasms has attracted widespread attention in the clinical setting. Although a variety of diagnostic and treatment approaches have been proposed, there are some limitations to their application. In recent years, the role of salivary exosomes in cancer has been increasingly studied. Salivary exosomes not only renew and regulate the biological behavior of tumor cells, such as malignant proliferation, migration, and invasion, but they also serve as ideal markers for early diagnosis of diseases and may represent an effective therapeutic target. This article reviews the current research on salivary exosomes in malignant neoplasms.
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Affiliation(s)
- Yongqin Deng
- Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Yujie Cao
- Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Liuqian Wang
- Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Dong Ye
- Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People's Republic of China
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Jin C, Shi L, Li K, Liu W, Qiu Y, Zhao Y, Zhao B, Li Z, Li Y, Zhu Q. Mechanism of tumor‑derived extracellular vesicles in regulating renal cell carcinoma progression by the delivery of MALAT1. Oncol Rep 2021; 46:187. [PMID: 34278501 PMCID: PMC8298989 DOI: 10.3892/or.2021.8138] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Renal cell carcinoma (RCC) is a major healthcare burden globally. Tumor-derived extracellular vesicles (EVs) contribute to the formation of a pro-metastatic microenvironment. In the present study, we explored the role and mechanism of RCC cell 786-O-derived EVs (786-O-EVs) in RCC. First, 786-O-EVs were extracted and identified, and EV internalization of RCC cells was observed. RCC cell malignant behaviors and long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression patterns were detected before and after 786-O-EV treatment. MALAT1 was intervened to evaluate RCC cell behaviors. The downstream mechanism involving MALAT1 was predicted. In addition, the relationship among MALAT1, transcription factor CP2 like 1 (TFCP2L1) and ETS proto-oncogene 1, transcription factor (ETS1) was analyzed. TFCP2L1 expression patterns were measured after 786-O-EV exposure. Tumor xenograft formation assay and lung metastasis model were adopted to verify the role of 786-O-EVs in vivo in RCC. It was found that 786-O-EVs could be internalized by RCC cells. 786-O-EVs promoted RCC cell malignant behaviors, accompanied by elevated MALAT1 expression levels. The 786-O-EVs with MALAT1 knockdown attenuated the promotive effect of sole 786-O-EVs on RCC cells. MALAT1 located ETS1 in the TFCP2L1 promoter and negatively regulated TFCP2L1, and ETS1 protein could specifically bind to MALAT1. 786-O-EVs enhanced the binding of ETS1 and the TFCP2L1 promoter and decreased TFCP2L1 expression. In vivo, 786-O-EVs promoted tumor growth and RCC lung metastasis, which was suppressed following inhibition of MALAT1. Our findings indicated that 786-O-EVs promoted RCC invasion and metastasis by transporting MALAT1 to promote the binding of transcription factor ETS1 and TFCP2L1 promoter.
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Affiliation(s)
- Chengluo Jin
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Linmei Shi
- School of Health Management, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Kunlun Li
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Wei Liu
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Yu Qiu
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Yakun Zhao
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Bai Zhao
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Zhexun Li
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Yifei Li
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
| | - Qingguo Zhu
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Nangang, Harbin, Heilongjiang 150086, P.R. China
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Costanzi E, Simioni C, Varano G, Brenna C, Conti I, Neri LM. The Role of Extracellular Vesicles as Shuttles of RNA and Their Clinical Significance as Biomarkers in Hepatocellular Carcinoma. Genes (Basel) 2021; 12:genes12060902. [PMID: 34207985 PMCID: PMC8230662 DOI: 10.3390/genes12060902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) have attracted interest as mediators of intercellular communication following the discovery that EVs contain RNA molecules, including non-coding RNA (ncRNA). Growing evidence for the enrichment of peculiar RNA species in specific EV subtypes has been demonstrated. ncRNAs, transferred from donor cells to recipient cells, confer to EVs the feature to regulate the expression of genes involved in differentiation, proliferation, apoptosis, and other biological processes. These multiple actions require accuracy in the isolation of RNA content from EVs and the methodologies used play a relevant role. In liver, EVs play a crucial role in regulating cell-cell communications and several pathophysiological events in the heterogeneous liver class of cells via horizontal transfer of their cargo. This review aims to discuss the rising role of EVs and their ncRNAs content in regulating specific aspects of hepatocellular carcinoma development, including tumorigenesis, angiogenesis, and tumor metastasis. We analyze the progress in EV-ncRNAs' potential clinical applications as important diagnostic and prognostic biomarkers for liver conditions.
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Affiliation(s)
- Eva Costanzi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (E.C.); (G.V.); (C.B.); (I.C.)
| | - Carolina Simioni
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy;
- Laboratory for Technologies of Advanced Therapies (LTTA)—Electron Microscopy Center, University of Ferrara, 44121 Ferrara, Italy
| | - Gabriele Varano
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (E.C.); (G.V.); (C.B.); (I.C.)
- Laboratory for Technologies of Advanced Therapies (LTTA)—Electron Microscopy Center, University of Ferrara, 44121 Ferrara, Italy
| | - Cinzia Brenna
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (E.C.); (G.V.); (C.B.); (I.C.)
- Laboratory for Technologies of Advanced Therapies (LTTA)—Electron Microscopy Center, University of Ferrara, 44121 Ferrara, Italy
| | - Ilaria Conti
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (E.C.); (G.V.); (C.B.); (I.C.)
| | - Luca Maria Neri
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (E.C.); (G.V.); (C.B.); (I.C.)
- Laboratory for Technologies of Advanced Therapies (LTTA)—Electron Microscopy Center, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: ; Tel.: +39-0532-455940
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49
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Xing M, Wang X, Kiken RA, He L, Zhang JY. Immunodiagnostic Biomarkers for Hepatocellular Carcinoma (HCC): The First Step in Detection and Treatment. Int J Mol Sci 2021; 22:6139. [PMID: 34200243 PMCID: PMC8201127 DOI: 10.3390/ijms22116139] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) exerts huge effects on the health burden of the world because of its high mortality and poor prognosis. HCC is often clinically detected late in patients. If HCC could be detected and treated earlier, the survival rate of patients will be greatly improved. Therefore, identifying specific biomarkers is urgent and important for HCC. The liver is also recognized as an immune organ. The occurrence of HCC is related to exacerbation of immune tolerance and/or immunosurveillance escape. The host immune system plays an important role in the recognition and targeting of tumor cells in cancer immunotherapy, as can be seen from the clinical success of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Thus, there is a pressing medical need to discover immunodiagnostic biomarkers specific to HCC for understanding the pathological mechanisms of HCC, especially for immunotherapy targets. We have reviewed the existing literature to summarize the immunodiagnostic markers of HCC, including autoantibodies against tumor-associated antigens (TAAs) and exosomes, to provide new insights into HCC and early detection of this deadly cancer.
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Affiliation(s)
- Mengtao Xing
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
| | - Xinzhi Wang
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Robert A. Kiken
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
| | - Ling He
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
| | - Jian-Ying Zhang
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
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50
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Gurunathan S, Kang MH, Qasim M, Khan K, Kim JH. Biogenesis, Membrane Trafficking, Functions, and Next Generation Nanotherapeutics Medicine of Extracellular Vesicles. Int J Nanomedicine 2021; 16:3357-3383. [PMID: 34040369 PMCID: PMC8140893 DOI: 10.2147/ijn.s310357] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/25/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of membrane-limited vesicles and multi-signal messengers loaded with biomolecules. Exosomes and ectosomes are two different types of EVs generated by all cell types. Their formation depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. Further, EV release is a fundamental process required for intercellular communication in both normal physiology and pathological conditions to transmit/exchange bioactive molecules to recipient cells and the extracellular environment. The unique structure and composition of EVs enable them to serve as natural nanocarriers, and their physicochemical properties and biological functions can be used to develop next-generation nano and precision medicine. Knowledge of the cellular processes that govern EVs biology and membrane trafficking is essential for their clinical applications. However, in this rapidly expanding field, much remains unknown regarding EV origin, biogenesis, cargo sorting, and secretion, as well as EV-based theranostic platform generation. Hence, we present a comprehensive overview of the recent advances in biogenesis, membrane trafficking, and functions of EVs, highlighting the impact of nanoparticles and oxidative stress on EVs biogenesis and release and finally emphasizing the role of EVs as nanotherapeutic agents.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Muhammad Qasim
- Center of Bioengineering and Nanomedicine, Department of Food Science, University of Otago, Dunedin, 9054, New Zealand
| | - Khalid Khan
- Science and Technology KPK, Peshawar, Pakistan
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
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