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Delshad M, Sanaei MJ, Mohammadi MH, Sadeghi A, Bashash D. Exosomal Biomarkers: A Comprehensive Overview of Diagnostic and Prognostic Applications in Malignant and Non-Malignant Disorders. Biomolecules 2025; 15:587. [PMID: 40305328 PMCID: PMC12024574 DOI: 10.3390/biom15040587] [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: 02/19/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker.
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Affiliation(s)
- Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
- Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan 1411718541, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
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Liu T, Cui Y, Ouyang Y, Wang M, Yue S. Exosomal CCT3 as a biomarker for diagnosis and immune therapy response in patients diagnosed with hepatocellular carcinoma. Dig Liver Dis 2025:S1590-8658(25)00301-9. [PMID: 40221386 DOI: 10.1016/j.dld.2025.03.022] [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: 07/24/2024] [Revised: 11/19/2024] [Accepted: 03/21/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the dominant type of liver cancer and is associated with a high mortality rate. However, HCC lacks biomarkers for diagnosis and immune therapy response. Tumor-derived exosomes (TDEs) carcinogen-specific molecules have been used for screening multiple biomarkers. This study aimed to identify new biomarkers for the diagnosis of HCC and response to immune checkpoint blockade (ICB) therapy. METHODS Analysis of differentially expressed genes (DEGs) in HCC and normal tissues was integrated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ExoCarta datasets. The expression of CCT3 was validated in samples from patients with HCC using quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC) techniques. RESULTS Exosomal CCT3 was identified as a potential biomarker with significant impact. The expression of CCT3 in different tumor stages and normal tissues adjacent to the tumors (NATs) was validated using qPCR, western blotting, and IHC. CCT3 expression significantly increased the number of activated natural killer cells in HCC, as confirmed by qPCR and IHC. CCT3 expression significantly increases the expression of immune checkpoints in HCC. HCC-derived exosomes significantly increase the enrichment of CCT3. CONCLUSION Exosomal CCT3 is a biomarker for diagnosis and ICB therapy of HCC via MYC pathway activation and immune infiltration.
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Affiliation(s)
- Tiange Liu
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; Nankai University Affiliated Eye Hospital, Nankai University, Tianjin, China; Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China
| | - Yanyan Cui
- The Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Yiben Ouyang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Meilin Wang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Shijing Yue
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
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Karaca Dogan B, Salman Yilmaz S, Izgi GN, Ozen M. Circulating non-coding RNAs as a tool for liquid biopsy in solid tumors. Epigenomics 2025; 17:335-358. [PMID: 40040488 PMCID: PMC11970797 DOI: 10.1080/17501911.2025.2467021] [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: 08/16/2024] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Solid tumors are significant causes of global mortality and morbidity. Recent research has primarily concentrated on finding pathology-specific molecules that can be acquired non-invasively and that can change as the disease progresses or in response to treatment. The focus of research has moved to RNA molecules that are either freely circulating in body fluids or bundled in microvesicles and exosomes because of their great stability in challenging environments, ease of accessibility, and changes in level in response to therapy. In this context, there are many non-coding RNAs that can be used for this purpose in liquid biopsies. Out of these, microRNAs have been extensively studied. However, there has been an increase of interest in studying long non-coding RNAs, piwi interacting RNAs, circular RNAs, and other small non-coding RNAs. In this article, an overview of the most researched circulating non-coding RNAs in solid tumors will be reviewed, along with a discussion of the significance of these molecules for early diagnosis, prognosis, and therapeutic targets. The publications analyzed were extracted from the PubMed database between 2008 and June 2024.
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Affiliation(s)
- Beyza Karaca Dogan
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Seda Salman Yilmaz
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
- Department of Medical Services and Techniques Medical Monitoring Techniques Pr. Vocational School of Health Services, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Gizem Nur Izgi
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Mustafa Ozen
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
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Molina-Pelayo FA, Zarate-Lopez D, García-Carrillo R, Rodríguez-Beas C, Íñiguez-Palomares R, Rodríguez-Mejía JL, Soto-Guzmán A, Velasco-Loyden G, Sierra-Martínez M, Virgen-Ortiz A, Sánchez-Pastor E, Magaña-Vergara NE, Baltiérrez-Hoyos R, Alamilla J, Chagoya de Sánchez V, Dagnino-Acosta A, Chávez E, Castro-Sánchez L. miRNAs-Set of Plasmatic Extracellular Vesicles as Novel Biomarkers for Hepatocellular Carcinoma Diagnosis Across Tumor Stage and Etiologies. Int J Mol Sci 2025; 26:2563. [PMID: 40141205 PMCID: PMC11942138 DOI: 10.3390/ijms26062563] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of miRNAs in Extracellular Vesicles (EVs) from HCC. miRNA expression in EVs was analyzed using HCC cell lines, circulating EVs from a Diethylnitrosamine (DEN)-induced liver tumor rat model, and plasma samples from HCC patients. Receiver Operating Characteristics (ROCs) were applied to evaluate the diagnostic accuracy of circulating EV miRNAs in patients. Five miRNAs (miR-183-5p, miR-19a-3p, miR-148b-3p, miR-34a-5p, and miR-215-5p) were consistently up-regulated in EVs across in vitro and in vivo HCC models. These miRNAs showed statistically significant differences in HCC patients stratified by TNM staging and Edmondson-Steiner grading compared to healthy controls. They also differentiated HCC patients with various etiologies from the control group and distinguished HCC patients, with or without liver cirrhosis, from cirrhotic and healthy individuals. Individually and as a panel, they demonstrated high sensitivity, specificity, and accuracy in identifying HCC patients. Their consistent upregulation across models and clinical samples highlights their robustness as biomarkers for HCC diagnosis, offering the potential for early disease management and prognosis.
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Affiliation(s)
- Francisco A. Molina-Pelayo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - David Zarate-Lopez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Rosendo García-Carrillo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - César Rodríguez-Beas
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - Ramón Íñiguez-Palomares
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - José L. Rodríguez-Mejía
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Adriana Soto-Guzmán
- Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico;
| | - Gabriela Velasco-Loyden
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Mónica Sierra-Martínez
- Unidad de investigación en Salud, Hospital Regional de Alta Especialidad de Ixtapaluca, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS-BIENESTAR), Ciudad de México 01020, Mexico;
| | - Adolfo Virgen-Ortiz
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Enrique Sánchez-Pastor
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Nancy E. Magaña-Vergara
- Facultad de Ciencias Químicas, Universidad de Colima, Coquimatlán 28400, Colima, Mexico;
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | | | - Javier Alamilla
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Victoria Chagoya de Sánchez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Adán Dagnino-Acosta
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Enrique Chávez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Luis Castro-Sánchez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
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Jeng LB, Chan WL, Teng CF. Independent prognostic significance of tissue and circulating microrna biomarkers in hepatocellular carcinoma. Discov Oncol 2025; 16:281. [PMID: 40056315 DOI: 10.1007/s12672-025-02043-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/04/2025] [Indexed: 03/10/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although many therapeutic modalities have been established for treating HCC patients, the outcomes of patients remain unsatisfactory. Development of independent prognostic biomarkers is thus an important need to allow for early diagnosis and timely treatment. MicroRNAs (miRNAs) are the most studied class of small non-coding RNAs. It has been shown that miRNAs play essential roles in the multiple steps of HCC tumorigenesis and progression. Furthermore, the baseline expression levels of many miRNAs are altered in tumor tissues and blood circulation of HCC patients. Therefore, miRNAs have emerged as independent biomarkers for the prediction of HCC prognosis. This review provides a comprehensive literature-based summary of tissue and circulating miRNA biomarkers with independent prognostic significance in HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung, 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung, 404, Taiwan
| | - Wen-Ling Chan
- Department of Public Health, College of Public Health, China Medical University, Taichung, 404, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Hsueh-Shih Rd., Northern Dist., Taichung, 404, Taiwan.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 404, Taiwan.
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Chen WJ, Dai YJ, Gu WH, Zhang CL, Wang YC. Exosomatic miR-1246 Promotes Hepatocellular Carcinoma Progression via FSTL5 and ERK/p38 MAPK Pathway. J Biochem Mol Toxicol 2025; 39:e70148. [PMID: 40067339 DOI: 10.1002/jbt.70148] [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: 09/24/2024] [Revised: 12/11/2024] [Accepted: 01/16/2025] [Indexed: 05/13/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Unfortunately, the effective targeted therapies for HCC are lacking at present. While the regulation of microRNA-1246 (miR-1246) has been identified in HCC, its specific mechanism in exosomes derived from HCC remains elusive. This study aimed to explore the regulation of tumor-derived exosome miR-1246 in HCC cell invasion, migration, proliferation, and epithelial-mesenchymal transition (EMT). METHODS Exosomes secreted by HepG2 cells were characterized via Western blotting, nanoparticle tracking analysis, and transmission electron microscopy, followed by transfection with a miR-1246 inhibitor. RT-qPCR was employed for measuring the miR-1246 levels. Also, the impacts of the exosome miR-1246 inhibitor on HepG2 cell migration, invasion, proliferation, and EMT were evaluated. RESULTS The findings revealed elevated miR-1246 levels in HCC tissues relative to adjacent non-cancerous tissues, with a greater enrichment of miR-1246 in HepG2-derived exosomes than in HepG2 cells. HCC cell invasion, migration, proliferation, and EMT were significantly enhanced by HCC-derived exosomes, while exosomes loaded with miR-1246 inhibitor inhibited these biological functions. Further mechanistic studies illustrated an association of the regulatory role of miR-1246 with FSTL5 and ERK/p38 MAPK signaling. CONCLUSION In conclusion, tumor-derived miR-1246 enters hepatocellular carcinoma cells in the form of exosomes and promotes cancer cell invasion, EMT, and migration. The potential mechanism of miR-1246 is potentially relevant to the targeted gene FSTL5 as well as the ERK/p38 signaling.
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Affiliation(s)
- Wen-Ju Chen
- Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Ying-Jie Dai
- Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Wan-Hong Gu
- Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chun-Ling Zhang
- Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yi-Chao Wang
- Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clin Mol Hepatol 2025; 31:S255-S284. [PMID: 39604328 PMCID: PMC11925447 DOI: 10.3350/cmh.2024.0541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.
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Affiliation(s)
- Jaeho Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica S Liu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Ekaterina K. Koltsova
- Smidt Heart Institute, Department of Medicine, Department of Biomedical Sciences, 8700 Beverly Blvd, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Li S, Cheng F, Zhang Z, Xu R, Shi H, Yan Y. The role of hepatocyte-derived extracellular vesicles in liver and extrahepatic diseases. Biomed Pharmacother 2024; 180:117502. [PMID: 39357327 DOI: 10.1016/j.biopha.2024.117502] [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: 07/21/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Extracellular vesicles (EVs) are vesicle-like bodies with a double membrane structure that are released from the cell membrane or secreted by cells into the extracellular environment. These include exosomes, microvesicles, and apoptotic bodies. There is growing evidence indicating that the composition of liver cell contents changes following injury. The quantity of EVs and the biologically active substances they carry vary depending on the condition of the liver cells. Hepatocytes utilize EVs to modulate the functions of different liver cells and transfer them to distant organs via the systemic circulation, thereby playing a crucial role in intercellular communication. This review provides a concise overview of the research on the effects and potential mechanisms of hepatocyte-derived EVs (Hep-EVs) on liver diseases and extrahepatic diseases under different physiological and pathological conditions. Common liver diseases discussed include non-alcoholic fatty liver disease (NAFLD), viral hepatitis, alcoholic liver disease, drug-induced liver damage, and liver cancer. Given that NAFLD is the most prevalent chronic liver disease globally, this review particularly highlights the use of hepatocyte-derived EVs in NAFLD for disease progression, diagnosis, and treatment.
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Affiliation(s)
- Shihui Li
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Fang Cheng
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Zhuan Zhang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Ruizi Xu
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Honglei Shi
- Wujin Hospital Affiliated With Jiangsu University, Changzhou Wujin People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213004, China; Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou 213017, China; Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou 213017, China.
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou 213017, China; Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou 213017, China.
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9
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Yu S, Jiang S, Zhou Y, Zhu Z, Yang X. Impact of Radiation on Exosomes in Regulating Tumor Immune Microenvironment. Adv Radiat Oncol 2024; 9:101549. [PMID: 39055959 PMCID: PMC11269846 DOI: 10.1016/j.adro.2024.101549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 02/04/2024] [Indexed: 07/28/2024] Open
Abstract
Purpose Exosomes have been shown to play a role in most, if not all, steps of cancer progression. We still lack a comprehensive understanding of the bidirectional communication of exosomes between tumor cells and immune cells. This article aims to explore how exosomes can influence cancer growth and how they are affected by radiation therapy. Methods and Materials We searched on PubMed and Web of Science on the impact of radiation on tumor derived exosomes and immune cell derived exosomes in tumor immune microenvironment. We screened all the related articles and summarized their main discoveries and important results. Results This article reviewed the effects of tumor derived exosomes and immune cell-derived exosomes on TME and tumor progression after radiotherapy, suggesting the dual effects of exosomes which may refer to clinical practice. Moreover, we retrospected the clinical applications based on tumor derived exosomes, including liquid biopsy, radio-resistance and drug delivery, and discussed the challenges and prospects. Conclusions Exosomes are important in cancer treatment, especially with radiation therapy. Learning more about them could lead to better treatments. However, there are still challenges to overcome. The review points out the need for more research in this area.
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Affiliation(s)
- Silai Yu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Shanshan Jiang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Yue Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
| | - Xi Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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10
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Shetti D, Mallela VR, Ye W, Sharif M, Ambrozkiewicz F, Trailin A, Liška V, Hemminki K. Emerging role of circulating cell-free RNA as a non-invasive biomarker for hepatocellular carcinoma. Crit Rev Oncol Hematol 2024; 200:104391. [PMID: 38795877 DOI: 10.1016/j.critrevonc.2024.104391] [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: 03/14/2024] [Revised: 04/30/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a severe neoplastic disease associated with high morbidity and mortality rates. HCC is often detected at advanced stages leading to ineffective curative treatments. Recently, liquid biopsy has emerged as a non-invasive method to identify highly specific HCC biomarkers in bodily fluids such as blood, serum, urine, and saliva. Circulating cell-free nucleic acids (cfNAs), particularly cell-free DNA (cfDNA) and cell-free RNA (cfRNA), have become promising candidates for biomarkers in liquid biopsy applications. While cfDNA presented significant challenges, researchers have turned their attention to cfRNA, which can be efficiently identified through various methods and is considered a potential biomarker for cancer diagnosis and prognosis. This review primarily focuses on studies related to detecting various cfRNA in body fluids as biomarkers. The aim is to provide a summary of available information to assist researchers in their investigations and the development of new diagnostic and prognostic tools.
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Affiliation(s)
- Dattatrya Shetti
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic.
| | - Venkata Ramana Mallela
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic
| | - Wenjing Ye
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic
| | - Mahyar Sharif
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University,Alej Svobody 1665/76, Pilsen 323 00, Czech Republic
| | - Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic
| | - Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic
| | - Václav Liška
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic; Department of Surgery, University Hospital in Pilsen and Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen 323 00, Czech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 323 00, Czech Republic; Department of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
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11
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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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12
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Liu Q, Zhang Q, Yao Z, Yi G, Kang Y, Qiu Y, Yang Y, Yuan H, Fu R, Sheng W, Cheng L, Wang W, Wang H, Peng C. Pushing Forward the DNA Walkers in Connection with Tumor-Derived Extracellular Vesicles. Int J Nanomedicine 2024; 19:6231-6252. [PMID: 38915916 PMCID: PMC11194468 DOI: 10.2147/ijn.s464895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/15/2024] [Indexed: 06/26/2024] Open
Abstract
Extracellular vesicles (EVs) are microparticles released from cells in both physiological and pathological conditions and could be used to monitor the progression of various pathological states, including neoplastic diseases. In various EVs, tumor-derived extracellular vesicles (TEVs) are secreted by different tumor cells and are abundant in many molecular components, such as proteins, nucleic acids, lipids, and carbohydrates. TEVs play a crucial role in forming and advancing various cancer processes. Therefore, TEVs are regarded as promising biomarkers for the early detection of cancer in liquid biopsy. However, the currently developed TEV detection methods still face several key scientific problems that need to be solved, such as low sensitivity, poor specificity, and poor accuracy. To overcome these limitations, DNA walkers have emerged as one of the most popular nanodevices that exhibit better signal amplification capability and enable highly sensitive and specific detection of the analytes. Due to their unique properties of high directionality, flexibility, and efficiency, DNA walkers hold great potential for detecting TEVs. This paper provides an introduction to EVs and DNA walker, additionally, it summarizes recent advances in DNA walker-based detection of TEVs (2018-2024). The review highlights the close relationship between TEVs and DNA walkers, aims to offer valuable insights into TEV detection and to inspire the development of reliable, efficient, simple, and innovative methods for detecting TEVs based on DNA walker in the future.
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Affiliation(s)
- Qingyi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Qiongdan Zhang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Zhijian Yao
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Gangqiang Yi
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Yeonseok Kang
- College of Korean Medicine, Wonkwang University, Jeonbuk, Korea
| | - Yixing Qiu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Yupei Yang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Hanwen Yuan
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Ronggeng Fu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Wenbing Sheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Lidong Cheng
- Hunan Yirentang Chinese Herbal Pieces Co., Ltd, Changde, People’s Republic of China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Huizhen Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Caiyun Peng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- Institute of Innovation and Applied Research in Chinese Medicine Hunan University of Chinese Medicine, Changsha, People’s Republic of China
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13
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Panettieri E, Campisi A, De Rose AM, Mele C, Giuliante F, Vauthey JN, Ardito F. Emerging Prognostic Markers in Patients Undergoing Liver Resection for Hepatocellular Carcinoma: A Narrative Review. Cancers (Basel) 2024; 16:2183. [PMID: 38927889 PMCID: PMC11201456 DOI: 10.3390/cancers16122183] [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: 03/12/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
In patients with hepatocellular carcinoma (HCC), liver resection is potentially curative. Nevertheless, post-operative recurrence is common, occurring in up to 70% of patients. Factors traditionally recognized to predict recurrence and survival after liver resection for HCC include pathologic factors (i.e., microvascular and capsular invasion) and an increase in alpha-fetoprotein level. During the past decade, many new markers have been reported to correlate with prognosis after resection of HCC: liquid biopsy markers, gene signatures, inflammation markers, and other biomarkers, including PIVKA-II, immune checkpoint molecules, and proteins in urinary exosomes. However, not all of these new markers are readily available in clinical practice, and their reproducibility is unclear. Liquid biopsy is a powerful and established tool for predicting long-term outcomes after resection of HCC; the main limitation of liquid biopsy is represented by the cost related to its technical implementation. Numerous patterns of genetic expression capable of predicting survival after curative-intent hepatectomy for HCC have been identified, but published findings regarding these markers are heterogenous. Inflammation markers in the form of prognostic nutritional index and different blood cell ratios seem more easily reproducible and more affordable on a large scale than other emerging markers. To select the most effective treatment for patients with HCC, it is crucial that the scientific community validate new predictive markers for recurrence and survival after resection that are reliable and widely reproducible. More reports from Western countries are necessary to corroborate the evidence.
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Affiliation(s)
- Elena Panettieri
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Andrea Campisi
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Agostino M. De Rose
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Caterina Mele
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Felice Giuliante
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Francesco Ardito
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
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14
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Agnihotram R, Dhar R, Dhar D, Purushothaman K, Narasimhan AK, Devi A. Fusion of Exosomes and Nanotechnology: Cutting-Edge Cancer Theranostics. ACS APPLIED NANO MATERIALS 2024; 7:8489-8506. [DOI: 10.1021/acsanm.4c01033] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Rohan Agnihotram
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Debolina Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Kaavya Purushothaman
- Department of Biomedical Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Ashwin Kumar Narasimhan
- Department of Biomedical Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
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15
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Gupta R, Gupta J, Roy S. Exosomes: Key Players for Treatment of Cancer and Their Future Perspectives. Assay Drug Dev Technol 2024; 22:118-147. [PMID: 38407852 DOI: 10.1089/adt.2023.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2024] Open
Affiliation(s)
- Reena Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Suchismita Roy
- Institute of Pharmaceutical Research, GLA University, Mathura, India
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16
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Cao L, Ouyang H. Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors. Front Oncol 2024; 14:1374742. [PMID: 38463229 PMCID: PMC10920350 DOI: 10.3389/fonc.2024.1374742] [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: 01/22/2024] [Accepted: 02/08/2024] [Indexed: 03/12/2024] Open
Abstract
Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, and lipids and can serve as messengers for intercellular communication. They play critical roles in the exchange of information between tumor cells and the tumor microenvironment (TME). The TME consists of mesenchymal cells and components of the extracellular matrix (ECM), with fibroblasts being the most abundant cell type in the tumor mesenchyme. Cancer-associated fibroblasts (CAFs) are derived from normal fibroblasts and mesenchymal stem cells that are activated in the TME. CAFs can secrete exosomes to modulate cell proliferation, invasion, migration, drug resistance, and other biological processes in tumors. Additionally, tumor cells can manipulate the function and behavior of fibroblasts through direct cell-cell interactions. This review provides a summary of the intercellular crosstalk between GI tumor cells and CAFs through exosomes, along with potential underlying mechanisms.
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Affiliation(s)
- Longyang Cao
- Department of Gastroenterology, The First Peoples' Hospital of Hangzhou Linan District, Hangzhou, China
| | - Hong Ouyang
- Department of Gastroenterology, The First Peoples' Hospital of Hangzhou Linan District, Hangzhou, China
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17
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Yoo JS, Kang MK. Clinical significance of exosomal noncoding RNAs in hepatocellular carcinoma: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:4. [PMID: 38325815 PMCID: PMC11812098 DOI: 10.12701/jyms.2023.01186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/20/2023] [Accepted: 12/30/2023] [Indexed: 02/09/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.
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Affiliation(s)
- Jae Sung Yoo
- Department of Gastroenterology and Hepatology, The Catholic University of Korea, Seoul St Mary’s Hospital, Seoul, Korea
| | - Min Kyu Kang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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18
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Soliman N, Saharia A, Abdelrahim M, Connor AA. Molecular profiling in the management of hepatocellular carcinoma. Curr Opin Organ Transplant 2024; 29:10-22. [PMID: 38038621 DOI: 10.1097/mot.0000000000001124] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to both summarize the current knowledge of hepatocellular carcinoma molecular biology and to suggest a framework in which to prospectively translate this knowledge into patient care. This is timely as recent guidelines recommend increased use of these technologies to advance personalized liver cancer care. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in hepatocellular carcinoma, largely owing to next generation sequencing technologies, and nascent efforts to translate these into contemporary practice. SUMMARY Early efforts of translating molecular profiling to hepatocellular carcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking are a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care.
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19
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Wu Y, Liu S, Fan Z, Tian Y, Zhang L, Liu S. Establishment and Validation of a Blood Test-based Nomogram to Diagnose Patients with AFP-negative HCC. Curr Cancer Drug Targets 2024; 24:556-564. [PMID: 38178672 DOI: 10.2174/0115680096264770231113103930] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/05/2023] [Accepted: 09/25/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide. Alpha-protein (AFP) is the most widely used blood biomarker for HCC. However, elevated serum AFP is only observed in part of HCC. AIMS This study aimed to develop an efficient nomogram model to distinguish patients with alpha- protein-negative HCC and liver cirrhosis. OBJECTIVES A total of 1130 patients (508 HCC patients + 622 cirrhosis patients) were enrolled in the training cohort. A total of 244 HCC patients and 246 cirrhosis patients were enrolled in the validation cohort. METHODS A total of 41 parameters about blood tests were analyzed with logistic regression. The nomogram was based on independent factors and validated both internally and externally. RESULTS Independent factors were eosinophils %, hemoglobin concentration distribution width, fibrinogen, platelet counts, total bile acid, and mitochondria aspartate aminotransferase. The calibration curve for the probability of HCC showed good agreement between prediction by nomogram and actual observation. The concordance index was 0.851. In the validation cohort, the nomogram distinguished HCC from liver cirrhosis with an area under the curve of receiver operating characteristic of 0.754. CONCLUSION This proposed nomogram was an accurate and useful method to distinguish patients with AFP-negative HCC from liver cirrhosis.
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Affiliation(s)
- Yujing Wu
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Shuang Liu
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Zhijuan Fan
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Yaqiong Tian
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Lei Zhang
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Shuye Liu
- The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, 83 Jintang Road, Hedong District, Tianjin, 300170, China
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20
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Ihlamur M, Kelleci K, Zengin Y, Allahverdiyev MA, Abamor EŞ. Applications of Exosome Vesicles in Different Cancer Types as Biomarkers. Curr Mol Med 2024; 24:281-297. [PMID: 36941811 DOI: 10.2174/1566524023666230320120419] [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: 07/15/2022] [Revised: 12/11/2022] [Accepted: 01/09/2023] [Indexed: 03/23/2023]
Abstract
One of the biggest challenges in the fight against cancer is early detection. Early diagnosis is vital, but there are some barriers such as economic, cultural, and personal factors. Considering the disadvantages of radiological imaging techniques or serological analysis methods used in cancer diagnosis, such as being expensive, requiring expertise, and being time-consuming, there is a need to develop faster, more reliable, and cost-effective diagnostic methods for use in cancer diagnosis. Exosomes, which are responsible for intercellular communication with sizes ranging from 30-120 nm, are naturally produced biological nanoparticles. Thanks to the cargo contents they carry, they are a potential biomarker to be used in the diagnosis of cancer. Exosomes, defined as extracellular vesicles of endosomal origin, are effective in cancer growth, progression, metastasis, and drug resistance, and changes in microenvironmental conditions during tumor development change exosome secretion. Due to their high cellular activity, tumor cells produce much higher exosomes than healthy cells. Therefore, it is known that the number of exosomes in body fluids is significantly rich compared to other cells and can act as a stand-alone diagnostic biomarker. Cancer- derived exosomes have received great attention in recent years for the early detection of cancer and the evaluation of therapeutic response. In this article, the content, properties, and differences of exosomes detected in common types of cancer (lung, liver, pancreas, ovaries, breast, colorectal), which are the leading causes of cancer-related deaths, are reviewed. We also discuss the potential utility of exosome contents as a biomarker for early detection, which is known to be important in targeted cancer therapy.
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Affiliation(s)
- Murat Ihlamur
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
- Biruni University, Vocational School, Department of Electronics and Automation, Istanbul, Turkey
| | - Kübra Kelleci
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
- Beykoz University, Vocational School, Department of Medical Services and Techniques, Istanbul, Turkey
| | - Yağmur Zengin
- Bogazici University, Biomedical Engineering Institute, Department of Biomedical Engineering, Istanbul, Turkey
| | - M Adil Allahverdiyev
- Institute of the V. Akhundov National Scientific Research Medical Prophylactic, Baku, Azerbaijan Republic
| | - Emrah Şefik Abamor
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
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21
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma. Expert Rev Mol Diagn 2024; 24:5-22. [PMID: 38059597 DOI: 10.1080/14737159.2023.2292642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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22
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Hajizadeh M, Hajizadeh F, Ghaffarei S, Amin Doustvandi M, Hajizadeh K, Yaghoubi SM, Mohammadnejad F, Khiabani NA, Mousavi P, Baradaran B. MicroRNAs and their vital role in apoptosis in hepatocellular carcinoma: miRNA-based diagnostic and treatment methods. Gene 2023; 888:147803. [PMID: 37716587 DOI: 10.1016/j.gene.2023.147803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/03/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with high invasive and metastatic capability. Although significant advances have been made in the treatment of HCC, the overall survival rate of patients is still low. It is essential to explore accurate biomarkers for early diagnosis and prognosis along with therapeutic procedures to increase the survival rate of these patients. Anticancer therapies can contribute to induce apoptosis for the elimination of cancerous cells. However, dysregulated apoptosis and proliferation signaling pathways lead to treatment resistance, a significant challenge in improving efficient therapies. MiRNAs, short non-coding RNAs, play crucial roles in the progression of HCC, which regulate gene expression through post-transcriptional inhibition and targeting mRNA degradation in cancers. Dysregulated expression of multiple miRNAs is associated with numerous biological processes, including cell proliferation, apoptosis, invasion and metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and drug resistance in HCC. This review summarizes the role and potential efficacy of miRNAs in promoting and inhibiting cell proliferation and apoptosis in HCC, as well as the role of miRNAs in therapy resistance in HCC.
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Affiliation(s)
- Masoumeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevil Ghaffarei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khadijeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyed Mohammad Yaghoubi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | | | - Pegah Mousavi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Yan R, Chen H, Selaru FM. Extracellular Vesicles in Hepatocellular Carcinoma: Progress and Challenges in the Translation from the Laboratory to Clinic. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1599. [PMID: 37763719 PMCID: PMC10534795 DOI: 10.3390/medicina59091599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/27/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023]
Abstract
Extracellular vesicles (EVs) play critical roles in intercellular communication by transporting bioactive cargo to recipient cells. EVs have been implicated in a range of physiological and pathological processes, including tumor progression, metastasis, immune modulation, and drug resistance. The objective of this review is to present a thorough overview of recent studies focusing on EVs in hepatocellular carcinoma (HCC), with an emphasis on their potential utility as diagnostic biomarkers as well as therapeutic agents. Initially, we explore the utility of EVs as diagnostic biomarkers for HCC, followed by a discussion of their potential as carriers of therapeutic payloads. Additionally, we delve into the emerging field of therapeutic EVs for modulating tumor immune responses. Through this review, our ultimate aim is to provide a comprehensive understanding of the opportunities and challenges in the clinical translation of EV research in the domain of HCC.
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Affiliation(s)
- Rong Yan
- Department of Surgical Oncology, the First Affiliated Hospital, Xi’an Jiaotong University College of Medicine, Xi’an 710061, China
| | - Haiming Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA;
| | - Florin M. Selaru
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA;
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21224, USA
- The Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD 21231, USA
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Qin Y, Tu X, Huang M, Ma C, Huang Q, Huang Q, Shu H, Ou C. Novel Long Noncoding RNAs, LINC01093 and MYLK-AS1, Serve as Potential Diagnostic and Prognostic Biomarkers or Hepatocellular Carcinoma. DNA Cell Biol 2023; 42:488-497. [PMID: 37527208 DOI: 10.1089/dna.2022.0566] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies worldwide. In this research, we aimed to identify long noncoding RNAs (lncRNAs) as biomarkers for HCC diagnosis and prognosis. lncRNA expression profiles were obtained from Gene Expression Omnibus and The Cancer Genome Atlas databases. The differentially expressed lncRNAs between HCC and adjacent tissues were analyzed with bioinformatic tools. Four lncRNAs with area under the curve of the receiver operating characteristic curve >0.9 were selected from both datasets. Univariate and Kaplan-Meier analyses were performed to obtain LINC01093, MYLK-AS1, and MCM3AP-AS1 as the optimal diagnostic and prognostic biomarkers. Finally, qPCR confirmed that LINC01093 and MYLK-AS1 were significantly differentially expressed in HCC and adjacent normal tissues. In general, we demonstrated that novel lncRNAs, LINC01093 and MYLK-AS1, could be used as potential diagnostic and prognostic biomarkers for HCC.
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Affiliation(s)
- Yanming Qin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Xin Tu
- Department of Clinical Laboratory, Liuzhou Municipal Liutie Central Hospital, Liuzhou, People's Republic of China
| | - Meifang Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Caifang Ma
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Qiongqing Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Qiqi Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Hong Shu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
| | - Chao Ou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning City, People's Republic of China
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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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Logozzi M, Orefice NS, Di Raimo R, Mizzoni D, Fais S. The Importance of Detecting, Quantifying, and Characterizing Exosomes as a New Diagnostic/Prognostic Approach for Tumor Patients. Cancers (Basel) 2023; 15:cancers15112878. [PMID: 37296842 DOI: 10.3390/cancers15112878] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/11/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Exosomes are extracellular vesicles (EVs) of nanometric size studied for their role in tumor pathogenesis and progression and as a new source of tumor biomarkers. The clinical studies have provided encouraging but probably unexpected results, including the exosome plasmatic levels' clinical relevance and well-known biomarkers' overexpression on the circulating EVs. The technical approach to obtaining EVs includes methods to physically purify EVs and characterize EVs, such as Nanosight Tracking Analysis (NTA), immunocapture-based ELISA, and nano-scale flow cytometry. Based on the above approaches, some clinical investigations have been performed on patients with different tumors, providing exciting and promising results. Here we emphasize data showing that exosome plasmatic levels are consistently higher in tumor patients than in controls and that plasmatic exosomes express well-known tumor markers (e.g., PSA and CEA), proteins with enzymatic activity, and nucleic acids. However, we also know that tumor microenvironment acidity is a key factor in influencing both the amount and the characteristics of the exosome released by tumor cells. In fact, acidity significantly increases exosome release by tumor cells, which correlates with the number of exosomes that circulate through the body of a tumor patient.
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Affiliation(s)
- Mariantonia Logozzi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Nicola Salvatore Orefice
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | | | - Davide Mizzoni
- ExoLab Italia, Tecnopolo d'Abruzzo, 67100 L'Aquila, Italy
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
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27
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Irmer B, Chandrabalan S, Maas L, Bleckmann A, Menck K. Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors. Cancers (Basel) 2023; 15:cancers15041307. [PMID: 36831648 PMCID: PMC9953862 DOI: 10.3390/cancers15041307] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Extracellular vesicles (EVs) are secreted by all living cells and are ubiquitous in every human body fluid. They are quite heterogeneous with regard to biogenesis, size, and composition, yet always reflect their parental cells with their cell-of-origin specific cargo loading. Since numerous studies have demonstrated that EV-associated proteins, nucleic acids, lipids, and metabolites can represent malignant phenotypes in cancer patients, EVs are increasingly being discussed as valuable carriers of cancer biomarkers in liquid biopsy samples. However, the lack of standardized and clinically feasible protocols for EV purification and characterization still limits the applicability of EV-based cancer biomarker analysis. This review first provides an overview of current EV isolation and characterization techniques that can be used to exploit patient-derived body fluids for biomarker quantification assays. Secondly, it outlines promising tumor-specific EV biomarkers relevant for cancer diagnosis, disease monitoring, and the prediction of cancer progression and therapy resistance. Finally, we summarize the advantages and current limitations of using EVs in liquid biopsy with a prospective view on strategies for the ongoing clinical implementation of EV-based biomarker screenings.
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Affiliation(s)
- Barnabas Irmer
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Suganja Chandrabalan
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Lukas Maas
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Annalen Bleckmann
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
- West German Cancer Center, University Hospital Münster, 48149 Munster, Germany
| | - Kerstin Menck
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
- Correspondence:
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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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29
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Zhou Z, Xu X, Liu Y, Liu Q, Zhang W, Wang K, Wang J, Yin Y. Liquid Biopsy in Hepatocellular Carcinoma. Methods Mol Biol 2023; 2695:213-225. [PMID: 37450121 DOI: 10.1007/978-1-0716-3346-5_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly neoplasms with a poor prognosis. Due to the significant tumor heterogeneity of HCC, alpha-fetoprotein (AFP) or liver biopsy has not yet met the clinical needs in terms of early diagnosis or determining prognosis. In recent years, liquid biopsy techniques that analyze tumor by-products released into the circulation have shown great potential. Its ability to monitor tumors in real time and respond to their global characteristics is expected to improve the management of HCC patients clinically. This review discusses some of the findings of a liquid biopsy in terms of diagnosis and prognosis of HCC.
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Affiliation(s)
- Zheyu Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoliang Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qiaoyu Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Kun Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jincheng Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yin Yin
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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30
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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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Hasheminasabgorji E, Mishan MA, Tabari MAK, Bagheri A. miR-638: A Promising Cancer Biomarker with Therapeutic Potential. Curr Mol Med 2023; 23:377-389. [PMID: 35382724 DOI: 10.2174/1566524022666220405125900] [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: 10/26/2021] [Revised: 02/03/2022] [Accepted: 02/16/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND There is an unmet need to improve the diagnosis of cancer with precise treatment strategies. Therefore, more powerful diagnostic, prognostic, and therapeutic biomarkers are needed to overcome tumor cells. microRNAs (miRNAs, miRs), as a class of small non-coding RNAs, play essential roles in cancer through the tumor-suppressive or oncogenic effects by post-transcriptional regulation of their targets. Many studies have provided shreds of evidence on aberrantly expressed miRNAs in numerous cancers and have shown that miRNAs could play potential roles as diagnostic, prognostic, and even therapeutic biomarkers in patients with cancers. Findings have revealed that miR-638 over or underexpression might play a critical role in cancer initiation, development, and progression. However, the mechanistic effects of miR-638 on cancer cells are still controversial. CONCLUSION In the present review, we have focused on the diagnostic, prognostic, and therapeutic potentials of miR-638 and discussed its mechanistic roles in various types of cancers.
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Affiliation(s)
- Elham Hasheminasabgorji
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Arnie Charbonneau Cancer Institute, Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mohammad Amir Mishan
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abouzar Bagheri
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Xue T, Yam JWP. Role of Small Extracellular Vesicles in Liver Diseases: Pathogenesis, Diagnosis, and Treatment. J Clin Transl Hepatol 2022; 10:1176-1185. [PMID: 36381103 PMCID: PMC9634776 DOI: 10.14218/jcth.2022.00008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/08/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022] Open
Abstract
Extracellular vesicles (EVs) are vesicular bodies that bud off from the cell membrane or are secreted virtually by all cell types. Small EVs (sEVs or exosomes) are key mediators of cell-cell communication by delivering their cargo, including proteins, lipids, or RNAs, to the recipient cells where they induce changes in signaling pathways and phenotypic properties. Tangible findings have revealed the pivotal involvement of sEVs in the pathogenesis of various diseases. On the bright side, they are rich sources of biomarkers for diagnosis, prognosis, treatment response, and disease monitoring. sEVs have high stability, biocompatibility, targetability, low toxicity, and are immunogenic in nature. Their intrinsic properties make sEVs an ideal delivery vehicle to be loaded with cargo for therapeutic interventions. Liver diseases are a major global health problem. This review aims to focus on the roles and mechanisms of sEVs in the pathogenesis of liver diseases, liver injury, liver failure, and liver cancer. sEVs are released not only by hepatocytes but also by stromal and immune cells in the microenvironment. Early detection of liver disease determines the chance for curative treatment and high survival of patients. This review focuses on the potential of circulating sEV cargo as specific and sensitive noninvasive biomarkers for the early detection and prognosis of liver diseases. In addition, the therapeutic use of sEVs derived from various cell types is discussed. Although sEVs hold promise for clinical applications, there are still challenges to be overcome by further research to bring utilization of sEVs into clinical practice.
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Affiliation(s)
- Tingmao Xue
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Judy Wai Ping Yam
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Correspondence to: Judy Wai Ping Yam, Department of Pathology, 7/F Block T, Queen Mary Hospital, Pokfulam, Hong Kong, China. ORCID: https://orcid.org/0000-0002-5637-121X. Tel: +852-22552681, Fax: +852-22185212, E-mail:
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Contributions and therapeutic potential of tumor-derived microRNAs containing exosomes to cancer progression. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19:670-681. [PMID: 35676420 DOI: 10.1038/s41575-022-00620-y] [Citation(s) in RCA: 163] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/20/2022] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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36
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Exosomes and cancer - Diagnostic and prognostic biomarkers and therapeutic vehicle. Oncogenesis 2022; 11:54. [PMID: 36109501 PMCID: PMC9477829 DOI: 10.1038/s41389-022-00431-5] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/08/2022] Open
Abstract
AbstractExosomes belong to a subpopulation of extracellular vesicles secreted by the dynamic multistep endocytosis process and carry diverse functional molecular cargoes, including proteins, lipids, nucleic acids (DNA, messenger and noncoding RNA), and metabolites to promote intercellular communication. Proteins and noncoding RNA are among the most abundant contents in exosomes; they have biological functions and are selectively packaged into exosomes. Exosomes derived from tumor, stromal and immune cells contribute to the multiple stages of cancer progression as well as resistance to therapy. In this review, we will discuss the biogenesis of exosomes and their roles in cancer development. Since specific contents within exosomes originate from their cells of origin, this property allows exosomes to function as valuable biomarkers. We will also discuss the potential use of exosomes as diagnostic and prognostic biomarkers or predictors for different therapeutic strategies for multiple cancers. Furthermore, the applications of exosomes as direct therapeutic targets or engineered vehicles for drugs are an important field of exosome study. Better understanding of exosome biology may pave the way to promising exosome-based clinical applications.
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Słomka A, Wang B, Mocan T, Horhat A, Willms AG, Schmidt-Wolf IGH, Strassburg CP, Gonzalez-Carmona MA, Lukacs-Kornek V, Kornek MT. Extracellular Vesicles and Circulating Tumour Cells - complementary liquid biopsies or standalone concepts? Theranostics 2022; 12:5836-5855. [PMID: 35966579 PMCID: PMC9373826 DOI: 10.7150/thno.73400] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/06/2022] [Indexed: 12/11/2022] Open
Abstract
Liquid biopsies do promise a lot, but are they keeping it? In the past decade, additional novel biomarkers qualified to be called like that, of which, some took necessary hurdles resulting in FDA approval and clinical use. Some others are since a while around, well known and were once regarded to be a game changer in cancer diagnosis or cancer screening. But, during their clinical use limitations were observed from statistical significance and questions raised regarding their robustness, that eventually led to be dropped from associated clinical guidelines for certain applications including cancer diagnosis. The purpose of this review isn't to give a broad overview of all current liquid biopsy as biomarkers, weight them and promise a brighter future in cancer prevention, but rather to take a deeper look on two of those who do qualify to be called liquid biopsies now or then. These two are probably of greatest interest conceptually and methodically, and likely have the highest chances to be in clinical use soon, with a portfolio extension over their original conceptual usage. We aim to dig deeper beyond cancer diagnosis or cancer screening. Actually, we aim to review in depth extracellular vesicles (EVs) and compare with circulating tumour cells (CTCs). The latter methodology is partially FDA approved and in clinical use. We will lay out similarities as taking advantage of surface antigens on EVs and CTCs in case of characterization and quantification. But drawing readers' attention to downstream application based on capture/isolation methodology and simply on their overall nature, here apparently being living material eventually recoverable as CTCs are vs. dead material with transient effects on recipient cell as in case of EVs. All this we try to bring in perspective, compare and conclude towards which future direction we are aiming for, or should aim for. Do we announce a winner between CTCs vs EVs? No, but we provide good reasons to intensify research on them.
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Affiliation(s)
- Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-067 Bydgoszcz, Poland
| | - Bingduo Wang
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany.,Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
| | - Tudor Mocan
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu, University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Adelina Horhat
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu, University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Arnulf G Willms
- Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany.,Department of General, Visceral and Vascular Surgery, German Armed Forces Hospital Hamburg, 22049 Hamburg, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
| | - Maria A Gonzalez-Carmona
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
| | - Veronika Lukacs-Kornek
- Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
| | - Miroslaw T Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany
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38
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Gonvers S, Tabrizian P, Melloul E, Dormond O, Schwartz M, Demartines N, Labgaa I. Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma? Front Oncol 2022; 12:940473. [PMID: 36033451 PMCID: PMC9402935 DOI: 10.3389/fonc.2022.940473] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Liver transplant (LT) is the most favorable treatment option for patients with early stage hepatocellular carcinoma (HCC). Numerous attempts have been pursued to establish eligibility criteria and select HCC patients for LT, leading to various systems that essentially integrate clinico-morphological variables. Lacking of sufficient granularity to recapitulate the biological complexity of the disease, all these alternatives display substantial limitations and are thus undeniably imperfect. Liquid biopsy, defined as the molecular analysis of circulating analytes released by a cancer into the bloodstream, was revealed as an incomparable tool in the management of cancers, including HCC. It appears as an ideal candidate to refine selection criteria of LT in HCC. The present comprehensive review analyzed the available literature on this topic. Data in the field, however, remain scarce with only 17 studies. Although rare, these studies provided important and encouraging findings highlighting notable prognostic values and supporting the contribution of liquid biopsy in this specific clinical scenario. These results underpinned the critical and urgent need to intensify and accelerate research on liquid biopsy, in order to determine whether and how liquid biopsy may be integrated in the decision-making of LT in HCC.
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Affiliation(s)
- Stéphanie Gonvers
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Parissa Tabrizian
- Recanati Miller Transplant Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, United States
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Olivier Dormond
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Myron Schwartz
- Recanati Miller Transplant Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, United States
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Ismail Labgaa
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
- *Correspondence: Ismail Labgaa,
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Yang S, Wang J, Wang S, Zhou A, Zhao G, Li P. Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review). Int J Oncol 2022; 61:91. [PMID: 35674180 PMCID: PMC9262158 DOI: 10.3892/ijo.2022.5381] [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] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 11/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy of hepatocytes accounting for 75-85% of primary hepatic carcinoma cases. Small extracellular vesicles (sEVs), previously known as exosomes with a diameter of 30-200 nm, can transport a variety of biological molecules between cells, and have been proposed to function in physiological and pathological processes. Recent studies have indicated that the cargos of sEVs are implicated in intercellular crosstalk among HCC cells, paratumor cells and the tumor microenvironment. sEV-encapsulated substances (including DNA, RNA, proteins and lipids) regulate signal transduction pathways in recipient cells and contribute to cancer initiation and progression in HCC. In addition, the differential expression of sEV cargos between patients facilitates the potential utility of sEVs in the diagnosis and prognosis of patients with HCC. Furthermore, the intrinsic properties of low immunogenicity and high stability render sEVs ideal vehicles for targeted drug delivery in the treatment of HCC. The present review article summarizes the carcinogenic and anti-neoplastic capacities of sEVs and discusses the potential and prospective diagnostic and therapeutic applications of sEVs in HCC.
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Affiliation(s)
- Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Jiaxin Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Anni Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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40
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Nie G, Lian N, Peng D, Lu J, Li B. Prognostic Value of Exosomal Noncoding RNA in Hepatocellular Carcinoma: A Meta-analysis. Carcinogenesis 2022; 43:754-765. [PMID: 35904534 DOI: 10.1093/carcin/bgac066] [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: 04/20/2022] [Revised: 06/29/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
High morbidity, recurrence and mortality make hepatocellular carcinoma (HCC) a leading cause of cancer-related burden and deaths. The lack of prognostic evaluation methods weakened the therapeutic efficacy for HCC. Exosomal noncoding RNAs (ncRNAs) play a key role in cancer development. Our meta-analysis aimed to assess the prognostic value of exosome-transferred noncoding RNAs in predicting the outcomes of patients with HCC. We obtained 16 articles from PubMed, Web of Science, Scopus and EMBASE up to 4 November 2021. The ncRNAs were divided into three parts：microRNAs (miRNA), long noncoding RNAs (lncRNA) and circular RNAs (circRNA). In the pooled hazard ratios (HRs), upregulated miRNAs were 3.06 (95% CI = 2.51-3.73), downregulated miRNAs were 3.28 (95% CI = 2.61-4.11), lncRNAs were 3.34 (95% CI = 1.87-5.96), and circRNAs were 1.76 (95% CI = 1.36-2.14). As the results of subgroup analysis, upregulated miRNAs had a pooled HR of 3.10 (95% CI = 1.66-5.81), and the HR of downregulated miRNAs was 3.04 (95% CI = 2.17-4.28) for multivariate analysis of overall survival (OS). Meanwhile, upregulated miRNAs had a pooled HR of 2.61 (95% CI = 1.89-3.60), and the HR of downregulated miRNAs was 3.77 (95% CI = 1.11-12.73) for multivariate analysis of other endpoints. Remarkably, miR-21 has a pooled HR of 2.48 (95%CI = 1.52-4.05, I 2 = 0) for disease-free survival (DFS). In conclusion, the expression of exosomal noncoding RNAs can be used to evaluate the prognosis of patients with HCC. Exosome-transferred miR-21 might serve as a potential prognostic biomarker in HCC.
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Affiliation(s)
- Guilin Nie
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Nan Lian
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
| | - Dingzhong Peng
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Jiong Lu
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Bei Li
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, China
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41
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Zhang Q, Li H, Liu Y, Li J, Wu C, Tang H. Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma. CURRENT ONCOLOGY (TORONTO, ONT.) 2022; 29:5383-5406. [PMID: 36005165 PMCID: PMC9406833 DOI: 10.3390/curroncol29080427] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 02/07/2023]
Abstract
Exosomes, extracellular vesicles with a diameter of 40 to 160 nm, are among the smallest extracellular vesicles released by cells. They deliver different cargoes, including proteins, DNAs, and RNAs, and facilitate communication between cells to coordinate a variety of physiological and pathological functions. Hepatocellular carcinoma (HCC) is the sixth common malignant tumor and the fourth leading cause of cancer-related death worldwide. Its molecular mechanism remains largely unknown, and there is a lack of reliable and noninvasive biomarkers for early diagnosis and prognosis prediction. Mounting evidence has shown that exosomes carry a variety of ncRNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which play critical roles in the occurrence and progression of HCC. In this review, we summarize the recent findings of exosomal miRNAs, lncRNAs, and circRNAs in HCC from their impact on the development of HCC to their potential applications in the diagnosis and treatment of HCC.
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Affiliation(s)
- Qian Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; (Q.Z.); (H.L.); (Y.L.)
| | - Hanlin Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; (Q.Z.); (H.L.); (Y.L.)
| | - Yang Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; (Q.Z.); (H.L.); (Y.L.)
| | - Jian Li
- School of Basic Medical Sciences, Chengdu University, Chengdu 610106, China;
| | - Chunling Wu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; (Q.Z.); (H.L.); (Y.L.)
- Correspondence: (C.W.); (H.T.)
| | - Hua Tang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; (Q.Z.); (H.L.); (Y.L.)
- Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou 646000, China
- Engineering, Informatics Fusion and Transformation Key Laboratory, Luzhou 646000, China
- Correspondence: (C.W.); (H.T.)
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Tsuchiya A, Natsui K, Ishii Y, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Terai S. Small extracellular vesicles and liver diseases: From diagnosis to therapy. World J Hepatol 2022; 14:1307-1318. [PMID: 36158910 PMCID: PMC9376785 DOI: 10.4254/wjh.v14.i7.1307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/20/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs), especially small EVs (sEVs) derived from liver cells, have been the focus of much attention in the normal physiology and pathogenesis of various diseases affecting the liver. sEVs are approximately 100 nm in size, enclosed within lipid bilayers, and are very stable. The lipids, proteins, and nucleic acids, including miRNAs, contained within these vesicles are known to play important roles in intercellular communication. This mini-review summarizes the application of sEVs. First, liver diseases and the related diagnostic markers are described, and the current active status of miRNA research in diagnosis of hepatocellular carcinoma (HCC) is reported. Second, the biodistribution and pharmacokinetics of sEVs are described, and the liver is highlighted as the organ with the highest accumulation of sEVs. Third, the relationship between sEVs and the pathogenesis of liver disorders is described with emphesis on the current active status of miRNA research in HCC recurrence and survival. Finally, the possibility of future therapy using sEVs from mesenchymal stem (stromal) cells for cirrhosis and other diseases is described.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata 951-8510, Japan
| | - Kazuki Natsui
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yui Ishii
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yohei Koseki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Nobutaka Takeda
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Kei Tomiyoshi
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Fusako Yamazaki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yuki Yoshida
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Shuji Terai
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
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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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Exosome-Mediated Immunosuppression in Tumor Microenvironments. Cells 2022; 11:cells11121946. [PMID: 35741075 PMCID: PMC9221707 DOI: 10.3390/cells11121946] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.
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45
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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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46
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Ran Z, Wu S, Ma Z, Chen X, Liu J, Yang J. Advances in exosome biomarkers for cervical cancer. Cancer Med 2022; 11:4966-4978. [PMID: 35578572 PMCID: PMC9761094 DOI: 10.1002/cam4.4828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 02/03/2023] Open
Abstract
Cervical cancer (CC) ranks as the fourth most frequently diagnosed malignancy in females worldwide. Exosomes are a subclass of extracellular vesicles released by nearly all types of cells that act as cargo transport vehicles, carrying proteins, and genetic material (such as miRNAs, long noncoding RNAs, and mRNAs) derived from their parent cells may affect receiving cells and thus have emerged as key players in several biological processes, including inflammatory pathways. In this review, we concentrated on the findings of exosome investigations in CC, particularly their components. They direct the actions of CC cells by inducing surface molecules associated with various biological pathways. We summarized the current knowledge of exosomal RNAs and proteins from CC cells and discussed the feasibility of exosomes as potential biomarkers for CC. We suggest that cancer-derived exosomes promote metastasis in CC by supporting EMT, controlling the proliferation, invasion, or migration of cancer cells, as well as influencing immune escape and aiding angiogenesis. Overall, cancer-derived exosomes are critical in the progression of CC, and further studies are necessary to advance our understanding of the clinical value of exosomes in CC.
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Affiliation(s)
- Zihan Ran
- Department of ResearchShanghai University of Medicine & Health Sciences Affiliated Zhoupu HospitalShanghaiChina,Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Shaobo Wu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Zijng Ma
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Xiuwen Chen
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Jing Liu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina
| | - Jingcheng Yang
- The Genius Medicine Consortium (TGMC)ShanghaiChina,State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer CenterFudan UniversityShanghaiChina,Greater Bay Area Institute of Precision MedicineGuangzhouChina
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Wang C, Liu J, Yan Y, Tan Y. Role of Exosomes in Chronic Liver Disease Development and Their Potential Clinical Applications. J Immunol Res 2022; 2022:1695802. [PMID: 35571570 PMCID: PMC9106457 DOI: 10.1155/2022/1695802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/18/2022] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) are vesicular bodies (40-1000 nm) with double-layer membrane structures released by different cell types into extracellular environments, including apoptosis bodies, microvesicles, and exosomes. Exosomes (30-100 nm) are vesicles enclosed by extracellular membrane and contain effective molecules of secretory cells. They are derived from intracellular multivesicular bodies (MVBs) that fuse with the plasma membrane and release their intracellular vesicles by exocytosis. Research has shown that almost all human cells could secrete exosomes, which have a certain relationship with corresponding diseases. In chronic liver diseases, exosomes release a variety of bioactive components into extracellular spaces, mediating intercellular signal transduction and materials transport. Moreover, exosomes play a role in the diagnosis, treatment, and prognosis of various chronic liver diseases as potential biomarkers and therapeutic targets. Previous studies have found that mesenchymal stem cell-derived exosomes (MSC-ex) could alleviate acute and chronic liver injury and have the advantages of high biocompatibility and low immunogenicity. In this paper, we briefly summarize the role of exosomes in the pathogenesis of different chronic liver diseases and the latest research progresses of MSC-ex as the clinical therapeutic targets.
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Affiliation(s)
- Chen Wang
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Jiangsu University, Zhenjiang, 212005 Jiangsu, China
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Jinwen Liu
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Yongmin Yan
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Youwen Tan
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Jiangsu University, Zhenjiang, 212005 Jiangsu, China
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48
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Newman LA, Muller K, Rowland A. Circulating cell-specific extracellular vesicles as biomarkers for the diagnosis and monitoring of chronic liver diseases. Cell Mol Life Sci 2022; 79:232. [PMID: 35397694 PMCID: PMC8995281 DOI: 10.1007/s00018-022-04256-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/02/2022] [Accepted: 03/17/2022] [Indexed: 11/30/2022]
Abstract
AbstractChronic liver diseases represent a burgeoning health problem affecting billions of people worldwide. The insufficient performance of current minimally invasive tools is recognised as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) have emerged as a rich source of circulating biomarkers closely linked to pathological processes in originating tissues. Here, we summarise the contribution of EVs to normal liver function and to chronic liver pathologies; and explore the use of circulating EV biomarkers, with a particular focus on techniques to isolate and analyse cell- or tissue-specific EVs. Such approaches present a novel strategy to inform disease status and monitor changes in response to treatment in a minimally invasive manner. Emerging technologies that support the selective isolation and analysis of circulating EVs derived only from hepatic cells, have driven recent advancements in EV-based biomarker platforms for chronic liver diseases and show promise to bring these techniques to clinical settings.
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Affiliation(s)
- Lauren A Newman
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Kate Muller
- Department of Gastroenterology and Hepatology, College of Medicine and Public Health, Flinders Medical Centre, Adelaide, SA, Australia
| | - Andrew Rowland
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
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49
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Li Z, Liang L, Duan W, Zhou C, Yang JJ. Non-linear relationship of gamma-glutamyl transpeptidase to lymphocyte count ratio with the recurrence of hepatocellular carcinoma with staging I-II: a retrospective cohort study. Infect Agent Cancer 2022; 17:16. [PMID: 35395799 PMCID: PMC8991940 DOI: 10.1186/s13027-022-00428-0] [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: 08/03/2021] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND High recurrence rate was a major factor for the poor postoperative prognosis of hepatocellular carcinoma (HCC) patients. The present study was intended to evaluate the association of gamma-glutamyl transpeptidase to lymphocyte count ratio (GLR) and the recurrence of HCC with staging I-II in Chinese. METHODS The retrospective cohort data was derived from the First Affiliated Hospital of Zhengzhou University from January 2014 to December 2018 on 496 patients who underwent radical resection of HCC with staging I-II. Multivariable Cox regression models were used to determine hazard ratios (HR) and 95% confidence interval (CI) for the recurrence of HCC with staging I-II of each GLR tertile category. The restricted cubic spline model was used to find out the threshold effect. RESULTS With the low tertile of GLR as the reference, multivariable-adjusted HR and 95% CI of the middle and high tertile categories were 1.748 (1.170-2.612) and 2.078 (1.339-3.227). In addition, there was a positive correlation (HR 1.002; 95% CI 1.001-1.004) and a non-liner relationship was found, whose point was 27.5. When the GLR was less than 27.5, the risk of recurrence increased, obviously with the increase in GLR levels (HR 1.041; 95% CI 1.014-1.068). CONCLUSIONS The GLR was independently associated with the recurrence of HCC patients with staging I-II. Furthermore, the relationship was positive and no-linear.
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Affiliation(s)
- Zeping Li
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Lili Liang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Wen Duan
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Chengmao Zhou
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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