|
1
|
Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
Collapse
Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| |
Collapse
|
|
2
|
Choi WJ, Nabavizadeh N. The potential of multi- and single-cancer blood-based early detection tests in liver cancer screening. J Gastrointest Oncol 2025; 16:711-718. [PMID: 40386614 PMCID: PMC12078824 DOI: 10.21037/jgo-24-686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/23/2025] [Indexed: 05/20/2025] Open
Abstract
Liver cancer is one of the most common causes of cancer deaths worldwide. Although fatal when diagnosed at an advanced stage, liver cancer has a favorable prognosis when identified at an earlier stage. Guidelines for liver cancer screening do exist, currently recommending the use of ultrasound with or without hematologic markers for early detection of liver cancer. However, studies have revealed shortcomings in the current state of liver cancer screenings such as underutilization stemming from lack of primary care education and logistical barriers for patients, suboptimal sensitivity of current screening methods, and lack of screening for lower risk individuals. A multitude of liquid biopsy tests that use circulating genomic analytes for early detection of cancers are currently under development and have the potential clinical implications in the early detection of liver cancer. In this overview, we highlight limitations of current liver cancer screenings and the ongoing development of multicancer early detection tests as well as cancer specific blood tests for liver cancer. As these multi-analyte blood tests hold promise in filling the gaps of current shortcomings of liver cancer screenings, it is imperative for primary care physicians, oncologists, and hepatologists involved in the screening process to be aware of ongoing studies and the further research necessary to ascertain several parameters such as the cost-benefit ratio, mortality reduction, and sensitivities of the blood tests.
Collapse
Affiliation(s)
- Won Jin Choi
- California Northstate University College of Medicine, Elk Grove, CA, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, School of Medicine, Oregon Health & Science University, Portland, OR, USA
| |
Collapse
|
|
3
|
Davis E, Ermi AG, Sarkar D. Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1375. [PMID: 40282551 PMCID: PMC12025727 DOI: 10.3390/cancers17081375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.
Collapse
Affiliation(s)
- Eva Davis
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Ali Gawi Ermi
- Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Cellular, Molecular and Genetic Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| |
Collapse
|
|
4
|
Wu ST, Zhu L, Feng XL, Wang HY, Li F. Strategies for discovering novel hepatocellular carcinoma biomarkers. World J Hepatol 2025; 17:101201. [PMID: 40027561 PMCID: PMC11866143 DOI: 10.4254/wjh.v17.i2.101201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/13/2024] [Accepted: 12/23/2024] [Indexed: 02/20/2025] Open
Abstract
Liver cancer, particularly hepatocellular carcinoma (HCC), remains a significant global health challenge due to its high mortality rate and late-stage diagnosis. The discovery of reliable biomarkers is crucial for improving early detection and patient outcomes. This review provides a comprehensive overview of current and emerging biomarkers for HCC, including alpha-fetoprotein, des-gamma-carboxy prothrombin, glypican-3, Golgi protein 73, osteopontin, and microRNAs. Despite advancements, the diagnostic limitations of existing biomarkers underscore the urgent need for novel markers that can detect HCC in its early stages. The review emphasizes the importance of integrating multi-omics approaches, combining genomics, proteomics, and metabolomics, to develop more robust biomarker panels. Such integrative methods have the potential to capture the complex molecular landscape of HCC, offering insights into disease mechanisms and identifying targets for personalized therapies. The significance of large-scale validation studies, collaboration between research institutions and clinical settings, and consideration of regulatory pathways for clinical implementation is also discussed. In conclusion, while substantial progress has been made in biomarker discovery, continued research and innovation are essential to address the remaining challenges. The successful translation of these discoveries into clinical practice will require rigorous validation, standardization of protocols, and cross-disciplinary collaboration. By advancing the development and application of novel biomarkers, we can improve the early detection and management of HCC, ultimately enhancing patient survival and quality of life.
Collapse
Affiliation(s)
- Shi-Tao Wu
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Li Zhu
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Xiao-Ling Feng
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Hao-Yu Wang
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Fang Li
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China.
| |
Collapse
|
|
5
|
Roberts LR. Surveillance for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:17-31. [PMID: 39608955 DOI: 10.1016/j.cld.2024.09.001] [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: 11/30/2024]
Abstract
This article reviews surveillance for the detection of early stage hepatocellular carcinoma, covering the rationale for surveillance, optimal selection of persons needing surveillance, methods and frequency of screening, strategies for addressing barriers to surveillance, and trends for future improvement in surveillance leading to more effective cancer control and improved patient outcomes. The importance of integrating liver cancer surveillance as a core component of national public health programs is emphasized. The impact of emerging technologies for identifying persons at risk, stratifying individual risk to improve the cost-effectiveness of surveillance programs, and improving the performance, accessibility, and convenience of surveillance are discussed.
Collapse
Affiliation(s)
- Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street Southwest, Rochester, MN 55905, USA.
| |
Collapse
|
|
6
|
Tu J, Wang B, Wang X, Huo K, Hu W, Zhang R, Li J, Zhu S, Liang Q, Han S. Current status and new directions for hepatocellular carcinoma diagnosis. LIVER RESEARCH 2024; 8:218-236. [PMID: 39958920 PMCID: PMC11771281 DOI: 10.1016/j.livres.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/17/2024] [Accepted: 12/01/2024] [Indexed: 02/18/2025]
Abstract
Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.
Collapse
Affiliation(s)
- Jinqi Tu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Bo Wang
- Animal Experimental Center, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Kugeng Huo
- Cyagen Biosciences (Guangzhou) Inc., Guangzhou, Guangdong, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Rongli Zhang
- Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| |
Collapse
|
|
7
|
Choi JH, Thung SN. Pathology and diagnostic approaches to well-differentiated hepatocellular lesions: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:5. [PMID: 39442859 PMCID: PMC11812079 DOI: 10.12701/jyms.2024.00766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or nonneoplastic lesions in which the cells closely resemble normal hepatocytes. These lesions often include focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule, dysplastic nodule, and well-differentiated hepatocellular carcinoma. The diagnosis of these lesions remains challenging because of their morphological similarities, particularly when examined using needle biopsy. The accurate diagnosis of WDHLs is crucial for patient management and prognosis. This review addresses the histopathological characteristics and diagnostic approaches of WDHLs.
Collapse
Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
|
8
|
Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023; 78:1922-1965. [PMID: 37199193 PMCID: PMC10663390 DOI: 10.1097/hep.0000000000000466] [Citation(s) in RCA: 659] [Impact Index Per Article: 329.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/01/2023] [Indexed: 05/19/2023]
Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Josep M. Llovet
- Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA
- Translational Research in Hepatic Oncology, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University of Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Mark Yarchoan
- Department of Medical Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Neil Mehta
- University of California, San Francisco, San Francisco, California, USA
| | | | - Laura A. Dawson
- Radiation Medicine Program/University Health Network, Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - Janice H. Jou
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon, USA
| | - Laura M. Kulik
- Northwestern Medical Faculty Foundation, Chicago, Illinois, USA
| | - Vatche G. Agopian
- The Dumont–University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Jorge A. Marrero
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Mishal Mendiratta-Lala
- Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
| | - Daniel B. Brown
- Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - William S. Rilling
- Division of Interventional Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Lipika Goyal
- Department of Medicine, Stanford School of Medicine, Palo Alto, California, USA
| | - Alice C. Wei
- Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Tamar H. Taddei
- Department of Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| |
Collapse
|
|
9
|
Liu Y, Han G, Gong J, Hua X, Zhu Q, Zhou S, Jiang L, Li Q, Liu S. Intramolecular fluorescence resonance energy transfer strategy for accurate detection of AFP-L3% and improved diagnosis of hepatocellular carcinoma. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 300:122950. [PMID: 37295202 DOI: 10.1016/j.saa.2023.122950] [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: 04/17/2023] [Revised: 05/17/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023]
Abstract
Early and accurate diagnosis of hepatocellular carcinoma (HCC) is of significant importance for improving the survival rate and quality of life for HCC patients. The combined detection of alpha-fetoprotein (AFP) and alpha-fetoprotein-L3 (AFP-L3), namely AFP-L3%, can greatly improve the accuracy of HCC diagnosis compared with AFP detection. Herein, we developed a novel intramolecular fluorescence resonance energy transfer (FRET) strategy for sequential detection of AFP and AFP-specific core fucose to improve the diagnosis accuracy of HCC. Firstly, fluorescence-labeled AFP aptamer (AFP Apt-FAM) was used to specifically recognize all AFP isoforms, and total AFP was quantitatively determined using fluorescence intensity of FAM. Then, 4-((4-(dimethylamino)phenyl)azo)benzoic acid (Dabcyl) labeled lectins (PhoSL-Dabcyl) were used to specifically recognize the core fucose expressed on AFP-L3 that does not bind to other AFP isoforms. The combination of FAM and Dabcyl on the same AFP molecule could generate FRET effect, thereby quenching the fluorescence signal of FAM and quantitatively determining AFP-L3. After that, AFP-L3% was calculated according to the ratio of AFP-L3 to AFP. With this strategy, the concentration of total AFP, AFP-L3 isoform as well as the AFP-L3% were sensitively detected. Detection limits of 0.66 and 0.186 ng/mL were obtained for AFP and AFP-L3 in human serum, respectively. Clinical human serum test results showed that AFP- L3 % test was more accurate than AFP assay to distinguish healthy people, HCC patients and benign liver disease patients. Therefore, the proposed strategy is simple, sensitive and selective, which can improve the accuracy of early diagnosis of HCC, and has good clinical application potential.
Collapse
Affiliation(s)
- Yu Liu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu, Sichuan 610068, China
| | - Gaohua Han
- Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China
| | - Jing Gong
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - Xin Hua
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
| | - Qian Zhu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Sisi Zhou
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Ling Jiang
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - Quan Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu, Sichuan 610068, China.
| | - Songqin Liu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| |
Collapse
|
|
10
|
Son JA, Weon JH, Baek GO, Ahn HR, Choi JY, Yoon MG, Cho HJ, Cheong JY, Eun JW, Kim SS. Circulating small extracellular vesicle-derived splicing factor 3b subunit 4 as a non-invasive diagnostic biomarker of early hepatocellular carcinoma. J Exp Clin Cancer Res 2023; 42:288. [PMID: 37899451 PMCID: PMC10614366 DOI: 10.1186/s13046-023-02867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/16/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer cases and related deaths. The purpose of this study was to assess the diagnostic value of splicing factor 3b subunit 4 (SF3B4) as a novel non-invasive biomarker for HCC and determine the association between SF3B4 expression and immune cell infiltration. METHODS An enzyme-linked immunosorbent assay (ELISA) was used to detect SF3B4 levels in plasma samples obtained from healthy controls (HCs) and patients with chronic hepatitis, liver cirrhosis, and HCC. The expression levels of autoantibodies that detect SF3B4 in the plasma samples of each group of patients were measured. Small extracellular vesicles (EVs) were isolated from patient sera, and the expression levels of EV-SF3B4 were measured using quantitative reverse transcription PCR. RESULTS ELISA results confirmed that the expression levels of SF3B4 proteins and autoantibodies in the plasma of patients with HCC were higher than those in HCs. However, their diagnostic performance was not better than that of alpha-fetoprotein (AFP). The mRNA expression of SF3B4 in serum EV increased but not in the buffy coat or serum of patients with HCC. Serum EV-SF3B4 displayed better diagnostic power than AFP for all stages of HCC (AUC = 0.968 vs. 0.816), including early-stage HCC (AUC = 0.960 vs. 0.842), and this was consistent in the external cohort. Single-cell RNA sequencing indicated that SF3B4 expression was correlated with myeloid-derived suppressor cells. The Tumor Immune Estimation Resource database reconfirmed the correlation between SF3B4 expression and immune cell infiltration in HCC. CONCLUSIONS SF3B4 may be associated with tumor immune infiltration in HCC, and EV-SF3B4 shows potential as a novel non-invasive diagnostic biomarker of HCC.
Collapse
Affiliation(s)
- Ju A Son
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Ji Hyang Weon
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Geum Ok Baek
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hye Ri Ahn
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Ji Yi Choi
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Moon Gyeong Yoon
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.
| |
Collapse
|
|
11
|
Wang J, Wang F, Wang N, Zhang MY, Wang HY, Huang GL. Diagnostic and Prognostic Value of Protein Post-translational Modifications in Hepatocellular Carcinoma. J Clin Transl Hepatol 2023; 11:1192-1200. [PMID: 37577238 PMCID: PMC10412711 DOI: 10.14218/jcth.2022.00006s] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 02/03/2023] [Accepted: 02/21/2023] [Indexed: 07/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high incidence and cancer mortality worldwide. Post-translational modifications (PTMs) of proteins have a great impact on protein function. Almost all proteins can undergo PTMs, including phosphorylation, acetylation, methylation, glycosylation, ubiquitination, and so on. Many studies have shown that PTMs are related to the occurrence and development of cancers. The findings provide novel therapeutic targets for cancers, such as glypican-3 and mucin-1. Other clinical implications are also found in the studies of PTMs. Diagnostic or prognostic value, and response to therapy have been identified. In HCC, it has been shown that glycosylated alpha-fetoprotein (AFP) has a higher detection rate for early liver cancer than conventional AFP. In this review, we mainly focused on the diagnostic and prognostic value of PTM, in order to provide new insights into the clinical implication of PTM in HCC.
Collapse
Affiliation(s)
- Jing Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Fangfang Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Ning Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Guo-Liang Huang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| |
Collapse
|
|
12
|
Shen EYL, U MRA, Cox IJ, Taylor-Robinson SD. The Role of Mass Spectrometry in Hepatocellular Carcinoma Biomarker Discovery. Metabolites 2023; 13:1059. [PMID: 37887384 PMCID: PMC10609223 DOI: 10.3390/metabo13101059] [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: 08/31/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the main liver malignancy and has a high mortality rate. The discovery of novel biomarkers for early diagnosis, prognosis, and stratification purposes has the potential to alleviate its disease burden. Mass spectrometry (MS) is one of the principal technologies used in metabolomics, with different experimental methods and machine types for different phases of the biomarker discovery process. Here, we review why MS applications are useful for liver cancer, explain the MS technique, and briefly summarise recent findings from metabolomic MS studies on HCC. We also discuss the current challenges and the direction for future research.
Collapse
Affiliation(s)
- Eric Yi-Liang Shen
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City 333, Taiwan
- Clinical Metabolomics Core Laboratory, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City 333, Taiwan
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
| | - Mei Ran Abellona U
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK
| | - I. Jane Cox
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences & Medicine, King’s College London, London SE5 8AF, UK
| | - Simon D. Taylor-Robinson
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
| |
Collapse
|
|
13
|
Taru MG, Lupsor-Platon M. Exploring Opportunities to Enhance the Screening and Surveillance of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease (NAFLD) through Risk Stratification Algorithms Incorporating Ultrasound Elastography. Cancers (Basel) 2023; 15:4097. [PMID: 37627125 PMCID: PMC10452922 DOI: 10.3390/cancers15164097] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.
Collapse
Affiliation(s)
- Madalina-Gabriela Taru
- Hepatology Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania;
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Monica Lupsor-Platon
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania
| |
Collapse
|
|
14
|
Silva MLS. Capitalizing glycomic changes for improved biomarker-based cancer diagnostics. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:366-395. [PMID: 37455827 PMCID: PMC10344901 DOI: 10.37349/etat.2023.00140] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/24/2023] [Indexed: 07/18/2023] Open
Abstract
Cancer serum biomarkers are valuable or even indispensable for cancer diagnostics and/or monitoring and, currently, many cancer serum markers are routinely used in the clinic. Most of those markers are glycoproteins, carrying cancer-specific glycan structures that can provide extra-information for cancer monitoring. Nonetheless, in the majority of cases, this differential feature is not exploited and the corresponding analytical assays detect only the protein amount, disregarding the analysis of the aberrant glycoform. Two exceptions to this trend are the biomarkers α-fetoprotein (AFP) and cancer antigen 19-9 (CA19-9), which are clinically monitored for their cancer-related glycan changes, and only the AFP assay includes quantification of both the protein amount and the altered glycoform. This narrative review demonstrates, through several examples, the advantages of the combined quantification of protein cancer biomarkers and the respective glycoform analysis, which enable to yield the maximum information and overcome the weaknesses of each individual analysis. This strategy allows to achieve higher sensitivity and specificity in the detection of cancer, enhancing the diagnostic power of biomarker-based cancer detection tests.
Collapse
Affiliation(s)
- Maria Luísa S. Silva
- Unidade de Aprendizagem ao Longo da Vida, Universidade Aberta, 1269-001 Lisboa, Portugal
| |
Collapse
|
|
15
|
Guan MC, Zhang SY, Ding Q, Li N, Fu TT, Zhang GX, He QQ, Shen F, Yang T, Zhu H. The Performance of GALAD Score for Diagnosing Hepatocellular Carcinoma in Patients with Chronic Liver Diseases: A Systematic Review and Meta-Analysis. J Clin Med 2023; 12:949. [PMID: 36769597 PMCID: PMC9918029 DOI: 10.3390/jcm12030949] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/28/2023] Open
Abstract
Background GALAD score, comprising five clinical parameters, is a predictive model developed for hepatocellular carcinoma (HCC) detection. Since its emergence, its diagnostic ability has been validated in different populations with a wide variation. Therefore, we conducted a meta-analysis to investigate its overall diagnostic performance in differentiating HCC in chronic liver diseases. Methods Eligible studies were searched in the Web of Science, PubMed, Scopus, Ovid, Cochrane Library, and Embase databases by 29 May 2022. Pooled sensitivity, pooled specificity, and area under the receiver operating characteristic curve (AUC) with the corresponding 95% confidence intervals (CI) were estimated. Results Fifteen original studies (comprising 19,021 patients) were included. For detecting any-stage HCC, GALAD score yielded an excellent ability, with pooled sensitivity, specificity, and AUC of 0.82 (95%CI: 0.78-0.85), 0.89 (95%CI: 0.85-0.91), and 0.92 (95%CI: 0.89-0.94), respectively. Notably, further analyses demonstrated a good diagnostic accuracy of GALAD score for identifying Barcelona Clinic Liver Cancer staging (BCLC) 0/A HCC, with a moderate sensitivity (0.73 (95%CI: 0.66-0.79)) and a high specificity (0.87 (95%CI: 0.81-0.91)); by contrast, only 38% of early-stage patients can be identified by alpha-fetoprotein, with an AUC value of 0.70 (95%CI: 0.66-0.74). Following subgroup analyses based on different HCC etiologies, higher sensitivities and AUC values were observed in subgroups with hepatitis C or non-viral liver diseases. For detecting BCLC 0/A HCC in the cirrhotic population, GALAD score had a pooled sensitivity, specificity, and AUC of 0.78 (95%CI: 0.66-0.87), 0.80 (95%CI: 0.72-0.87), and 0.86 (95%CI: 0.83-0.89). Conclusions We highlighted the superior diagnostic accuracy of GALAD score for detecting any-stage HCC with a high sensitivity and specificity, especially for early-stage HCC, with a relatively stable diagnostic performance. The addition of GALAD score into ultrasound surveillance may identify more HCC patients. Our findings imply the robust power of the GALAD score as a HCC screening or diagnostic tool, and it should be further validated by more studies with high quality.
Collapse
Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Shi-Yu Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Qian Ding
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Na Li
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Ting-Ting Fu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Gui-Xia Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Qian-Qian He
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai 200433, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310014, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| |
Collapse
|
|
16
|
Guan MC, Ouyang W, Liu SY, Sun LY, Chen WY, Tong XM, Zhu H, Yang T. Alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease: A multicenter analysis. Hepatobiliary Pancreat Dis Int 2022; 21:559-568. [PMID: 35643910 DOI: 10.1016/j.hbpd.2022.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 03/09/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Current surveillance strategies for hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) are insufficient. This study aimed to investigate the diagnostic performance of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and their combinations in HCC underlying NAFLD patients. METHODS Serologic AFP, AFP-L3, and PIVKA-II levels in NAFLD patients with and without HCC were measured. By receiver operating characteristic (ROC) analyses, the area under the curve (AUC), sensitivity, and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations. RESULTS This study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls. The elevation of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls (all P < 0.001). When they were analyzed individually, PIVKA-II showed the best performance in diagnosing any-stage HCC with an AUC of 0.869, followed by AFP (0.763; vs. PIVKA-II, P < 0.001) and AFP-L3 (0.689; vs. PIVKA-II, P < 0.001). When they were analyzed in combination, AFP + PIVKA-II yielded the highest AUC (0.906), followed by AFP + PIVKA-II + AFP-L3 (0.904; vs. AFP + PIVKA-II, P = 0.086), PIVKA-II + AFP-L3 (0.881; vs. AFP + PIVKA-II, P < 0.001), and AFP + AFP-L3 (0.759; vs. AFP + PIVKA-II, P < 0.001). Similar findings were obtained in the subgroup with early-stage NAFLD-HCC, as well as the non-cirrhotic subgroup. CONCLUSIONS These data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD, and the combination of AFP + PIVKA-II significantly improved the diagnostic accuracy of NAFLD-HCC.
Collapse
Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wei Ouyang
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Si-Yu Liu
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China
| | - Li-Yang Sun
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Wei-Yue Chen
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China; The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Department of Interventional Radiology, Zhejiang University Lishui Hospital, Lishui 323000, China
| | - Xiang-Min Tong
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China; Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China
| | - Hong Zhu
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - Tian Yang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
| |
Collapse
|
|
17
|
Phan TH, Chi Nguyen VT, Thi Pham TT, Nguyen VC, Ho TD, Quynh Pham TM, Tran TH, Nguyen TD, Khang Le ND, Nguyen TH, Duong ML, Bach HPT, Kim VV, Pham TA, Nguyen BT, Vo Nguyen TN, Nguyen TD, Bieu Phu DT, Huu Phan BH, Nguyen DS, Truong DK, Do TTT, Giang H, Nguyen HN, Phan MD, Tran LS. Circulating DNA methylation profile improves the accuracy of serum biomarkers for the detection of nonmetastatic hepatocellular carcinoma. Future Oncol 2022; 18:4399-4413. [PMID: 36786635 DOI: 10.2217/fon-2022-1218] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Aim: This study exploited hepatocellular carcinoma (HCC)-specific circulating DNA methylation profiles to improve the accuracy of a current screening assay for HCC patients in high-risk populations. Methods: Differentially methylated regions in cell-free DNA between 58 nonmetastatic HCC and 121 high-risk patients with liver cirrhosis or chronic hepatitis were identified and used to train machine learning classifiers. Results: The model could distinguish HCC from high-risk non-HCC patients in a validation cohort, with an area under the curve of 0.84. Combining these markers with the three serum biomarkers (AFP, lectin-reactive AFP, des-γ-carboxy prothrombin) in a commercial test, μTASWako®, achieved an area under the curve of 0.87 and sensitivity of 68.8% at 95.8% specificity. Conclusion: HCC-specific circulating DNA methylation markers may be added to the available assay to improve the early detection of HCC.
Collapse
Affiliation(s)
| | - Van Thien Chi Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | | | - Van-Chu Nguyen
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | - Tan Dat Ho
- MEDIC Medical Center, Ho Chi Minh City, Vietnam
| | - Thi Mong Quynh Pham
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Thanh-Huong Tran
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | - Thanh Dat Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Nguyen Duy Khang Le
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Trong-Hieu Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | | | | | - Van-Vu Kim
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | | | | | | | | | | | | | - Duy-Sinh Nguyen
- Department of Oncology, Faculty of Medicine, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam
| | | | | | - Hoa Giang
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Hoai-Nghia Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Minh-Duy Phan
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Le Son Tran
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| |
Collapse
|
|
18
|
Lesko P, Chovanec M, Mego M. Biomarkers of disease recurrence in stage I testicular germ cell tumours. Nat Rev Urol 2022; 19:637-658. [PMID: 36028719 DOI: 10.1038/s41585-022-00624-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 11/09/2022]
Abstract
Stage I testicular cancer is a disease restricted to the testicle. After orchiectomy, patients are considered to be without disease; however, the tumour is prone to relapse in ~4-50% of patients. Current predictive markers of relapse, which are tumour size and invasion to rete testis (in seminoma) or lymphovascular invasion (in non-seminoma), have limited clinical utility and are unable to correctly predict relapse in a substantial proportion of patients. Adjuvant therapeutic strategies based on available biomarkers can lead to overtreatment of 50-85% of patients. Discovery and implementation of novel biomarkers into treatment decision making will help to reduce the burden of adjuvant treatments and improve patient selection for adjuvant therapy.
Collapse
Affiliation(s)
- Peter Lesko
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia.
| |
Collapse
|
|
19
|
Phosphorylated Proteins from Serum: A Promising Potential Diagnostic Biomarker of Cancer. Int J Mol Sci 2022; 23:ijms232012359. [PMID: 36293212 PMCID: PMC9604268 DOI: 10.3390/ijms232012359] [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: 09/22/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a fatal disease worldwide. Each year ten million people are diagnosed around the world, and more than half of patients eventually die from it in many countries. A majority of cancer remains asymptomatic in the earlier stages, with specific symptoms appearing in the advanced stages when the chances of adequate treatment are low. Cancer screening is generally executed by different imaging techniques like ultrasonography (USG), mammography, CT-scan, and magnetic resonance imaging (MRI). Imaging techniques, however, fail to distinguish between cancerous and non-cancerous cells for early diagnosis. To confirm the imaging result, solid and liquid biopsies are done which have certain limitations such as invasive (in case of solid biopsy) or missed early diagnosis due to extremely low concentrations of circulating tumor DNA (in case of liquid biopsy). Therefore, it is essential to detect certain biomarkers by a noninvasive approach. One approach is a proteomic or glycoproteomic study which mostly identifies proteins and glycoproteins present in tissues and serum. Some of these studies are approved by the Food and Drug Administration (FDA). Another non-expensive and comparatively easier method to detect glycoprotein biomarkers is by ELISA, which uses lectins of diverse specificities. Several of the FDA approved proteins used as cancer biomarkers do not show optimal sensitivities for precise diagnosis of the diseases. In this regard, expression of phosphoproteins is associated with a more specific stage of a particular disease with high sensitivity and specificity. In this review, we discuss the expression of different serum phosphoproteins in various cancers. These phosphoproteins are detected either by phosphoprotein enrichment by immunoprecipitation using phosphospecific antibody and metal oxide affinity chromatography followed by LC-MS/MS or by 2D gel electrophoresis followed by MALDI-ToF/MS analysis. The updated knowledge on phosphorylated proteins in clinical samples from various cancer patients would help to develop these serum phophoproteins as potential diagnostic/prognostic biomarkers of cancer.
Collapse
|
|
20
|
Lin Y, Zong X, Li M, Wan S, Yu H, Wei X. Marked elevation of serum alpha-fetoprotein following Clonorchis sinensis infection: A rare case report. LIVER RESEARCH 2022; 6:45-49. [PMID: 39959805 PMCID: PMC11791854 DOI: 10.1016/j.livres.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/11/2022] [Accepted: 03/02/2022] [Indexed: 11/18/2022]
Abstract
Clonorchiasis, also known as the liver fluke disease, is caused by eating raw freshwater fish or shrimps that contain Clonorchis sinensis cyst larvae, which mainly involves the hepatobiliary system. Chronic abdominal pain and distention, loss of appetite, and hepatomegaly are the most common clinical manifestation. Persistent infection with Clonorchis sinensis would result in chronic inflammation, epithelial hyperplasia, and periductal fibrosis and even progress to cholangiocarcinoma. Nevertheless, the majority of the infected people are asymptomatic or mildly symptomatic, contributing to its high misdiagnosis rate. Alpha-fetoprotein (AFP) is a well-known biomarker for hepatocellular carcinoma (HCC). A high level of AFP can also be caused by several benign diseases, causing confusion and influencing treatment decisions. So far, clonorchiasis with a markedly elevated level of AFP has been rarely reported. We present a case of clonorchiasis with a high level of AFP in a 52-year-old man. We hope to raise clinical awareness of this food-borne disease. Clonorchiasis should be considered in patients with extremely high levels of AFP, excluding HCC and germ cell tumors, especially if the patient has a history of ingesting raw freshwater fish or shrimps.
Collapse
Affiliation(s)
- Ying Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaodan Zong
- Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mingkai Li
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Sizhe Wan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongsheng Yu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiuqing Wei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| |
Collapse
|
|
21
|
Hanif H, Ali MJ, Susheela AT, Khan IW, Luna-Cuadros MA, Khan MM, Lau DTY. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol 2022; 28:216-229. [PMID: 35110946 PMCID: PMC8776528 DOI: 10.3748/wjg.v28.i2.216] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/26/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.
Collapse
Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Ammu T Susheela
- Internal Medicine, Loyola MacNeal Hospital, Berwyn, PA 60402, United States
| | - Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Maria Alejandra Luna-Cuadros
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| |
Collapse
|
|
22
|
Lee HA, Lee YR, Lee YS, Jung YK, Kim JH, An H, Yim HJ, Jeen YT, Yeon JE, Byun KS, Seo YS. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma. World J Gastroenterol 2021; 27:4687-4696. [PMID: 34366629 PMCID: PMC8326250 DOI: 10.3748/wjg.v27.i28.4687] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/10/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated. AIM To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis. METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit. RESULTS In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results. CONCLUSION The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.
Collapse
Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yoo Ra Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Hyunggin An
- Department of Biostatistics, Korea University Anam Hospital, Seoul 02841, South Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| |
Collapse
|
|
23
|
Sun X, He Z, Guo L, Wang C, Lin C, Ye L, Wang X, Li Y, Yang M, Liu S, Hua X, Wen W, Lin C, Long Z, Zhang W, Li H, Jian Y, Zhu Z, Wu X, Lin H. ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer. J Exp Clin Cancer Res 2021; 40:149. [PMID: 33931075 PMCID: PMC8086123 DOI: 10.1186/s13046-021-01932-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/30/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. METHODS In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients' samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. RESULTS ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. CONCLUSION Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.
Collapse
Affiliation(s)
- Xiaoqing Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Zhenyu He
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Ling Guo
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Caiqin Wang
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, People's Republic of China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Liping Ye
- Department of Experimental Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Xiaoqing Wang
- Department of Radiotherapy, Nanfang Hospital, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Meisongzhu Yang
- Department of Physiology, Sun Yat-sen University, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Sailan Liu
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xin Hua
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Wen Wen
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Chao Lin
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Zhiqing Long
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Wenwen Zhang
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Han Li
- Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Yunting Jian
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Ziyuan Zhu
- Department of General surgery, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150, Guangdong, People's Republic of China
| | - Xianqiu Wu
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, Guangdong, People's Republic of China.
| | - Huanxin Lin
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China.
| |
Collapse
|
|
24
|
Dimopoulos YP, Winslow ER, He AR, Ozdemirli M. Hepatocellular carcinoma with biliary and neuroendocrine differentiation: A case report. World J Clin Oncol 2021; 12:262-271. [PMID: 33959479 PMCID: PMC8085510 DOI: 10.5306/wjco.v12.i4.262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/07/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver tumors with dual differentiations [combined hepatocellular carcinoma (HCC) and cholangiocarcinoma] are common. However, liver tumors that exhibit hepatocellular, biliary, and neuroendocrine differentiation are exceedingly rare, with only three previous case reports in the literature.
CASE SUMMARY A 65-year-old female with a previous history of hepatitis C and a distant history of low grade, well-differentiated rectal neuroendocrine tumor was found to have two liver lesions in segment 4 and segment 7 on imaging. Serum alpha-fetoprotein and chromogranin A were elevated. Biopsy of the larger lesion in segment 4 revealed a high-grade tumor, with morphologic and immunohistochemical features of a neuroendocrine tumor. Given the previous history of rectal neuroendocrine tumor, imaging investigation, serologic markers, and biopsy findings, metastatic neuroendocrine tumor was considered. Subsequent regional resection of these hepatic lesions revealed the segment 4 lesion to be a HCC with additional biliary and neuroendocrine differentiation and the segment 7 lesion to be a cholangiocarcinoma with neuroendocrine differentiation. Follow-up of the patient revealed disease recurrence in the dome of the liver and metastasis in retro-pancreatic lymph nodes. The patient eventually expired due to complications of chemotherapy.
CONCLUSION HCC cases with additional biliary and neuroendocrine differentiation are exceedingly rare, posing a diagnostic challenge for clinicians and pathologists.
Collapse
Affiliation(s)
- Yiannis Petros Dimopoulos
- Department of Pathology and Laboratory Medicine, Medstar Georgetown University Hospital, Washington, DC 20007, United States
| | - Emily R Winslow
- Medstar Center for Liver and Pancreas Surgery, Medstar Georgetown University Hospital, Washington, DC 20007, United States
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC 20007, United States
| | - Metin Ozdemirli
- Department of Pathology and Laboratory Medicine, Medstar Georgetown University Hospital, Washington, DC 20007, United States
| |
Collapse
|
|
25
|
Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
Collapse
Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
26
|
Zhang J, Ten Dijke P, Wuhrer M, Zhang T. Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer. Protein Cell 2021; 12:89-106. [PMID: 32583064 PMCID: PMC7862465 DOI: 10.1007/s13238-020-00741-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022] Open
Abstract
Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-β (TGF-β). TGF-β bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely, N-glycans, O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-β signaling components regulates TGF-β secretion, bioavailability and TGF-β receptor function. Then, we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-β signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.
Collapse
Affiliation(s)
- Jing Zhang
- Oncode Institute and Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Tao Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
27
|
Risk Factors and Biomarkers for Chronic Hepatitis B Associated Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22020479. [PMID: 33418899 PMCID: PMC7825109 DOI: 10.3390/ijms22020479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 02/08/2023] Open
Abstract
Globally, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality. This is, in part, due to delayed diagnosis and limited therapeutic options with more advanced stages of the disease. Given the prognostic importance of early diagnosis, novel methods for early detection are in need. Unlike most other cancer types, tissue is not required to diagnose HCC and is frequently avoided given the inherent risks of liver biopsy, so less invasive methods of obtaining tumor material are currently under investigation. Material shed from tumors into the periphery are being investigated for their potential to both surveil and diagnose patients for HCC. These materials include circulating tumor cells, DNA, RNA, and exosomes, and are collectively termed a “liquid biopsy”. In this review article, we discuss the evolving literature regarding the different risk factors for HCC and the types of emerging novel biomarkers that show promise in the prevention and early diagnosis of HCC within the context of HBV infection.
Collapse
|
|
28
|
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is an increasingly common disease with liver transplant (LT) the best long-term therapy for early stage disease. We will review the data for assessing risk and managing recurrence for patients undergoing LT for HCC. AREAS COVERED In this review, we will provide an overview of methods of patient risk stratification in the post-transplant period, the data around surveillance for HCC recurrence, and the evidence for and against post-LT adjuvant treatment strategies. Finally, we will provide data regarding treatment options for patients with HCC recurrence after LT. Using an extensive search of original papers and society guidelines, this paper provides a comprehensive review of the data for assessing risk and managing recurrence for patients undergoing LT for HCC. EXPERT OPINION The development of multiple post-transplant prognostic scoring systems have allowed for improved assessment of recurrence risk and stratification of patients. However, the ability to translate this information into surveillance and therapeutic strategies that improve patient outcomes still have to be fully demonstrated. Post-LT immunosuppression strategies have been implemented in order to attempt to reduce this risk. Evidence-based strategies for managing recurrent HCC are evolving. We expect that with further understanding of individual patient characteristics will allow for optimal therapeutic selection.
Collapse
Affiliation(s)
- Daniel Hoffman
- Department of Surgery, University of California , San Francisco, CA, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California , San Francisco, CA, USA
| |
Collapse
|
|
29
|
Chen W, Wang R, Li D, Zuo C, Wen P, Liu H, Chen Y, Fujita M, Wu Z, Yang G. Comprehensive Analysis of the Glycome and Glycoproteome of Bovine Milk-Derived Exosomes. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:12692-12701. [PMID: 33137256 DOI: 10.1021/acs.jafc.0c04605] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Bovine milk-derived exosomes (BMDEs) have potential applications in the pharmaceutical industry as drug delivery carriers. A comprehensive analysis of protein glycosylation in exosomes is necessary to elucidate the process of targeted delivery. In this work, free oligosaccharides (FOSs), O-glycans, and N-glycans in BMDEs and whey were first analyzed through multiple derivation strategies. In summary, 13 FOSs, 44 O-glycans, and 94 N-glycans were identified in bovine milk. To analyze site-specific glycosylation of glycoproteins, a one-step method was used to enrich and characterize intact glycopeptides. A total of 1359 proteins including 114 glycoproteins were identified and most of these were located in the exosomes. Approximately 95 glycopeptides were initially discovered and 5 predicted glycosites were confirmed in BMDEs. Collectively, these findings revealed the characterization and distribution of glycans and glycoproteins in BMDEs, providing insight into the potential applications of BMDEs in drug delivery and food science.
Collapse
Affiliation(s)
- Wenyan Chen
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Rong Wang
- School of Medicine, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Dan Li
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Chenyang Zuo
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Piaopiao Wen
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Haili Liu
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Yongquan Chen
- School of Medicine, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Morihisa Fujita
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Zhimeng Wu
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Ganglong Yang
- The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education; School of Biotechnology, Jiangnan University, Wuxi 214122, China
| |
Collapse
|
|
30
|
Abstract
Patients with cirrhosis of the liver have a very high risk for developing hepatocellular carcinoma (HCC). Therefore, this group of patients should undergo surveillance to improve mortality. Better tools for stratifying the risk of HCC among patients with cirrhosis are needed. The best strategy for surveillance is the combination of alpha-fetoprotein and ultrasound of the liver every 6 months. This strategy shows a sensitivity of approximately 65% and a specificity of 90%, and importantly, has been shown to improve mortality in these patients. Balancing benefits and harms should be performed when deciding to proceed with surveillance.
Collapse
Affiliation(s)
- Jorge A Marrero
- UT Southwestern Medical Center, Professional Office Building 1, Suite 520L, 5959 Harry Hines Boulevard, Dallas, TX 75390-8887, USA.
| |
Collapse
|
|
31
|
Aglycosylated antibody-producing mice for aglycosylated antibody-lectin coupled immunoassay for the quantification of tumor markers (ALIQUAT). Commun Biol 2020; 3:636. [PMID: 33128033 PMCID: PMC7599229 DOI: 10.1038/s42003-020-01363-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 10/06/2020] [Indexed: 12/21/2022] Open
Abstract
Targeting aberrant glycoforms has been validated for in vitro cancer diagnostic development, and several assays are currently in routine clinical use. Because N-glycans in Fc region of antibodies show cross-reactivity with various lectins, high-quality aglycosylated antibodies are exceptionally important for immunoassay platform-based quantitative measurements. Previously, aglycosylated antibody acquisition relied on incomplete, uneconomical and onerous enzymatic and chemical methods. Here, we edited four murine immunoglobulin G genes using adenine base-editing and homology-directed recombination (HDR)-mediated gene editing methods to generate aglycosylated antibody-producing mice. Resulting aglycosylated antibodies showed required analytical performances without compromised protein stability. Thus, this aglycosylated monoclonal antibody-lectin coupled immunoassay for the quantification of tumour markers (ALIQUAT) method can provide a robust, versatile and accessible immunoassay platform to quantify specific glycoforms in precision cancer diagnostics. Moreover, the engineered mice can be used as a host to produce various aglycosylated antibodies in a convenient and robust fashion, thereby expanding in vitro diagnostic development opportunities that utilize glycoforms as a disease-specific biomarkers. Lee et al. describe the generation of aglycosylated antibody-producing mice. These aglycosylated antibodies, lacking glycans prevent unwanted interactions with the lectins, and are used as reagents in a tool they developed called ALIQUAT. This aglycosylated antibody and lectin-based immunoassay diagnostic platform can be used to detect disease specific glycan biomarkers.
Collapse
|
|
32
|
Rubén LC, Laura MR, Almudena FB, Emilio GM. Glycan array analysis of Pholiota squarrosa lectin and other fucose-oriented lectins. Glycobiology 2020; 31:459-476. [PMID: 33021632 DOI: 10.1093/glycob/cwaa093] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/14/2022] Open
Abstract
The α(1,6)fucose residue attached to the N-glycoprotein core is suspected to play an essential role in the progression of several types of cancer. Lectins remain the first choice for probing glycan modifications, although they may lack specificity. Thus, efforts have been made to identify new lectins with a narrower core fucose (CF) detection profile. Here, we present a comparison of the classical Aleuria aurantia lectin (AAL), Lens culinaris agglutinin (LCA) and Aspergillus oryzae lectin (AOL) with the newer Pholiota squarrosa lectin (PhoSL), which has been described as being specific for core fucosylated N-glycans. To this end, we studied the binding profiles of the four lectins using mammalian glycan arrays from the Consortium of Functional Glycomics. To validate their glycan specificity, we probed AOL, LCA and PhoSL in western-blot assays using protein extracts from eight common colorectal cancer (CRC) lines and colorectal biopsies from a small cohort of patients with CRC. The results showed that (i) LCA and PhoSL were the most specific lectins for detecting the presence of CF in a concentration-dependent manner; (ii) PhoSL exhibited the highest N-glycan sequence restriction, with preferential binding to core fucosylated paucimannosidic-type N-glycans, (iii) the recognition ability of PhoSL was highly influenced by the presence of terminal N-acetyl-lactosamine; (iv) LCA bound to paucimannosidic, bi-antennary and tri-antennary core fucosylated N-glycans and (v) AOL and AAL exhibited broader specificity towards fucosylation. Together, our results support the choice of LCA as the most appropriate lectin for CF detection, as validated in protein extracts from CRC cell lines and tissue specimens from patients with CRC.
Collapse
Affiliation(s)
- López-Cortés Rubén
- Doctoral Program in Methods and Applications in Life Sciences, Faculty of Biology, Universidade de Vigo, Campus Lagoas-Marcosende, Vigo, Pontevedra, Galicia ES36310, Spain
| | - Muinelo-Romay Laura
- Liquid Biopsy Analysis Unit, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), CIBERONC, Travesía da Choupana, Santiago de Compostela, A Coruña, Galicia ES15706, Spain
| | - Fernández-Briera Almudena
- Molecular Biomarkers, Biomedical Research Centre (CINBIO), Universidade de Vigo, Campus Lagoas-Marcosende, Vigo, Pontevedra, Galicia ES36310, Spain
| | - Gil Martín Emilio
- Nutrition and Food Science Group, Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Universidade de Vigo. Campus Lagoas-Marcosende, Vigo, Pontevedra, Galicia ES36310, Spain
| |
Collapse
|
|
33
|
Shah PA, Onken A, Ishtiaq R, Maqsood MH, Patel SS, Campoverde Reyes KJ, Herskovits AZ, Lau DTY. A challenging case of alpha-fetoprotein-result discrepancies in a patient with chronic hepatitis B. Gastroenterol Rep (Oxf) 2020; 8:484-486. [PMID: 33447392 PMCID: PMC7793204 DOI: 10.1093/gastro/goaa052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 05/23/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Pir A Shah
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Allison Onken
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Rizwan Ishtiaq
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Muhammad H Maqsood
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Shyam S Patel
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Karen J Campoverde Reyes
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Adrianna Z Herskovits
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daryl T Y Lau
- Department of Medicine, Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
34
|
Wang X, Zhang Y, Yang N, He H, Tao X, Kou C, Jiang J. Evaluation of the Combined Application of AFP, AFP-L3%, and DCP for Hepatocellular Carcinoma Diagnosis: A Meta-analysis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5087643. [PMID: 33015170 PMCID: PMC7519464 DOI: 10.1155/2020/5087643] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/25/2020] [Accepted: 09/03/2020] [Indexed: 12/24/2022]
Abstract
The role of α-fetoprotein (AFP) in the surveillance and diagnosis of hepatocellular carcinoma (HCC) has been questioned in recent years due to its low sensitivity and specificity. In addition to AFP, several new serum biomarkers, such as lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP), have also been identified as useful HCC serological markers. However, the exact diagnostic value of the combinations of these biomarkers for detecting HCC in patients with liver disease remains unclear. Thus, we performed the current meta-analysis to assess performance of AFP+AFP-L3%+DCP for diagnosing HCC. Studies were systematically searched in PubMed, Embase, the Cochrane Library, CNKI, and WanFang Data databases. After full-text evaluation, 13 studies from 11 articles focusing on the combination of the three serum biomarkers for HCC detection were enrolled. Random-effects models were used due to the presence of heterogeneity. The pooled sensitivity and specificity for AFP+AFP-L3%+DCP were 88% and 79%, respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.91, and the diagnostic odds ratio (DOR) was 28.33 (95% CI 16.78-47.83). Subgroup analysis showed that the pooled sensitivity and specificity of AFP+AFP-L3%+DCP in the diagnosis of HCC versus cirrhosis patients were 0.81 and 0.82, respectively. In conclusion, the combination of AFP, AFP-L3%, and DCP may prove to be useful in the diagnosis and screening of HCC.
Collapse
Affiliation(s)
- Xueying Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Yangyu Zhang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Na Yang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Hua He
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xuerong Tao
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Changgui Kou
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
35
|
Li XQ, Wang X, Zhao DW, Sun J, Liu JJ, Lin DD, Yang G, Liu H, Xia ZY, Jia CY, Li HJ. Application of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in hepatocellular carcinoma. World J Surg Oncol 2020; 18:219. [PMID: 32828123 PMCID: PMC7443289 DOI: 10.1186/s12957-020-01996-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver, and its morbidity and mortality have been increasing in recent years. The early diagnosis and prompt treatment of small HCC are crucial to improve the prognosis and quality of life of patients. In China, hepatitis B virus infection is the main cause. HCC with a single tumor nodule of ≤ 3 cm in diameter, or HCC with a number of nodules, in which each nodule is ≤ 2 cm in diameter, with a total diameter of ≤ 3 cm, is considered as small HCC. The MRI liver-specific contrast agent can detect small HCC at the early stage. This has important clinical implications for improving the survival rate of patients. MAIN BODY Gd-EOB-DTPA-enhanced MRI can significantly improve the sensitivity and specificity of the detection of HBV-related small hepatocellular carcinoma, providing an important basis for the clinical selection of appropriate personalized treatment. Gd-EOB-DTPA-enhanced MRI can reflect the degree of HCC differentiation, and the evaluation of HCC on Gd-EOB-DTPA-enhanced MRI would be helpful for the selection of the treatment and prognosis of HCC patients. The present study reviews the progress of the application of Gd-EOB-DTPA in the early diagnosis of small HCC, its clinical treatment, the prediction of the degree of differentiation, and the assessment of recurrence and prognosis of HCC, including the pharmacoeconomics and application limitations of Gd-EOB-DTPA. The value of the application of HCC with the Gd-EOB-DTPA was summarized to provide information for improving the quality of life and prolonging the survival of patients. CONCLUSION Gd-EOB-DTPA-enhanced MRI has the diagnostic capability for small HCC with a diameter of ≤ 2 cm. This will have a broader application prospect in the early diagnosis of small liver cancer with a diameter of ≤ 1 cm in the future. The relationship between GD-EOB-DTPA-MRI and the degree of HCC differentiation has a large research space, and Gd-EOB-DTPA is expected to become a potential tool for the preoperative prediction and postoperative evaluation of HCC, which would be beneficial for more appropriate treatments for HCC patients.
Collapse
Affiliation(s)
- Xue-Qin Li
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Xing Wang
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Da-Wei Zhao
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Jun Sun
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Jiao-Jiao Liu
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Dong-Dong Lin
- Department of Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Guang Yang
- Department of Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Hui Liu
- Department of Pathology,Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Zhen-Ying Xia
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Cui-Yu Jia
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Hong-Jun Li
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China.
| |
Collapse
|
|
36
|
Beudeker BJB, Boonstra A. Circulating biomarkers for early detection of hepatocellular carcinoma. Therap Adv Gastroenterol 2020; 13:1756284820931734. [PMID: 32647536 PMCID: PMC7325534 DOI: 10.1177/1756284820931734] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/11/2020] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths worldwide. HCC patients face a dismal prognosis because symptoms usually appear in an advanced stage of disease. The detection of early stage HCC allows for curative surgical treatment and therefore saves lives. Specific non-invasive or diagnostic markers for HCC may represent a valuable tool for detecting these tumors at an early stage. The clinically most established serological biomarker alpha-fetoprotein shows only limited diagnostic performance, however novel candidate biomarkers and biomarker panels for detecting HCC at early stages of development are being studied. In this review we will discuss the findings of these studies.
Collapse
Affiliation(s)
- Boris J. B. Beudeker
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | | |
Collapse
|
|
37
|
Benhammou JN, Lin J, Hussain SK, El-Kabany M. Emerging risk factors for nonalcoholic fatty liver disease associated hepatocellular carcinoma. HEPATOMA RESEARCH 2020; 6:35. [PMID: 32685690 PMCID: PMC7367098 DOI: 10.20517/2394-5079.2020.16] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.
Collapse
Affiliation(s)
- Jihane N. Benhammou
- Pfleger Liver Institute, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Jonathan Lin
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Shehnaz K. Hussain
- Department of Epidemiology, Fielding School of Public Health, University of California, CA 90095, USA
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mohamed El-Kabany
- Pfleger Liver Institute, University of California Los Angeles, Los Angeles, CA 90095, USA
| |
Collapse
|
|
38
|
Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment. Cells 2020; 9:1370. [PMID: 32492896 PMCID: PMC7349517 DOI: 10.3390/cells9061370] [Citation(s) in RCA: 315] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.
Collapse
Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina;
- Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
| | - Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina;
| | - Mário G. Pessôa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
| |
Collapse
|
|
39
|
The diagnostic value of serum DSA-TRF in hepatocellular carcinoma. Glycoconj J 2020; 37:231-240. [DOI: 10.1007/s10719-019-09906-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/04/2019] [Accepted: 12/30/2019] [Indexed: 12/11/2022]
|
|
40
|
Gautam AK, Sharma D, Sharma J, Saini KC. Legume lectins: Potential use as a diagnostics and therapeutics against the cancer. Int J Biol Macromol 2020; 142:474-483. [PMID: 31593731 DOI: 10.1016/j.ijbiomac.2019.09.119] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/16/2019] [Accepted: 09/16/2019] [Indexed: 12/17/2022]
Abstract
Legume lectins are carbohydrate-binding protein and widely distributed in a variety of species of leguminous plants and have drawn increased attention toward cancer. Nowadays, the lectins have been studied for the screening of potential biomarkers which increased its importance in cancer research. Few plant lectins have been shown to destroy cancer cells, suggesting that lectins may have biological potential in cancer treatments. In this review, we present a focused outline of legume lectins in descriptive their complex anti-cancer mechanisms on the bases of their properties of recognition and interacting specifically with carbohydrates binding sites. Existing reports suggested the binding of lectins to cancerous cells with their cell surface markers speculated by histochemistry in vitro and in vivo. In this review, we illuminate the use of legume lectins as a natural source for diagnostics and therapeutics purpose against cancer.
Collapse
Affiliation(s)
- Ajay Kumar Gautam
- Department of Plant Sciences, Central University of Punjab, Bathinda 151001, India
| | - Divakar Sharma
- Department of Biochemistry, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282004, India.
| | | | - Khem Chand Saini
- Centre for Biosciences, Central University of Punjab, Bathinda, Punjab 151001, India
| |
Collapse
|
|
41
|
α-Fetoprotein (AFP)-L3% and transforming growth factor B1 (TGFB1) in prognosis of hepatocellular carcinoma after radiofrequency. EGYPTIAN LIVER JOURNAL 2019. [DOI: 10.1186/s43066-019-0008-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Numerous hepatocellular carcinoma (HCC) biomarkers have been assessed in the diagnosis and prognosis of HCC. The aim of this study was to assess the value of α-fetoprotein (AFP)-L3% and transforming growth factor B1 (TGFB1) as prognostic markers in hepatocellular carcinoma after radiofrequency ablation (RFA). This observational cohort study included 40 patients with HCC diagnosed by triphasic computed tomography criteria indicated for radiofrequency ablation. Serum AFP, AFP-L3%, and TGFB1 were measured in all patients before and 3 months after radiofrequency ablation.
Results
Statistically significant lower levels of TGFB1, AFP, and AFP-L3% were noted in the HCC patients after radiofrequency ablation. Significant lower levels of TGFB1, AFP, and AFP-L3% were found in the no recurrence group in comparison to the recurrence group. The cutoff value of TGFB1 > 56.87 ng/mL, AFP > 74.9 ng/mL, and AFP-L3% > 8.5% was the best in the discrimination of tumor recurrence with sensitivity of 85.7%, 57.1%, and 100%; specificity of 54.6%, 84.9%, and 100%; and diagnostic accuracy of 64.5%, 69%, and 100%, respectively.
Conclusion
TGFB1 and AFP-L3% are good prognostic markers for HCC. They could be used to monitor the response of HCC to treatment.
Collapse
|
|
42
|
Study of serum microRNA19a and microRNA223 as potential biomarkers for early diagnosis of hepatitis C virus-related hepatocellular carcinoma. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
43
|
Zhu J, Warner E, Parikh ND, Lubman DM. Glycoproteomic markers of hepatocellular carcinoma-mass spectrometry based approaches. MASS SPECTROMETRY REVIEWS 2019; 38:265-290. [PMID: 30472795 PMCID: PMC6535140 DOI: 10.1002/mas.21583] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 10/19/2018] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most-common cause of cancer-related death worldwide. Most cases of HCC develop in patients that already have liver cirrhosis and have been recommended for surveillance for an early onset of HCC. Cirrhosis is the final common pathway for several etiologies of liver disease, including hepatitis B and C, alcohol, and increasingly non-alcoholic fatty liver disease. Only 20-30% of patients with HCC are eligible for curative therapy due primarily to inadequate early-detection strategies. Reliable, accurate biomarkers for HCC early detection provide the highest likelihood of curative therapy and survival; however, current early-detection methods that use abdominal ultrasound and serum alpha fetoprotein are inadequate due to poor adherence and limited sensitivity and specificity. There is an urgent need for convenient and highly accurate validated biomarkers for HCC early detection. The theme of this review is the development of new methods to discover glycoprotein-based markers for detection of HCC with mass spectrometry approaches. We outline the non-mass spectrometry based methods that have been used to discover HCC markers including immunoassays, capillary electrophoresis, 2-D gel electrophoresis, and lectin-FLISA assays. We describe the development and results of mass spectrometry-based assays for glycan screening based on either MALDI-MS or ESI analysis. These analyses might be based on the glycan content of serum or on glycan screening for target molecules from serum. We describe some of the specific markers that have been developed as a result, including for proteins such as Haptoglobin, Hemopexin, Kininogen, and others. We discuss the potential role for other technologies, including PGC chromatography and ion mobility, to separate isoforms of glycan markers. Analyses of glycopeptides based on new technologies and innovative softwares are described and also their potential role in discovery of markers of HCC. These technologies include new fragmentation methods such as EThcD and stepped HCD, which can identify large numbers of glycopeptide structures from serum. The key role of lectin extraction in various assays for intact glycopeptides or their truncated versions is also described, where various core-fucosylated and hyperfucosylated glycopeptides have been identified as potential markers of HCC. Finally, we describe the role of LC-MRMs or lectin-FLISA MRMs as a means to validate these glycoprotein markers from patient samples. These technological advancements in mass spectrometry have the potential to lead to novel biomarkers to improve the early detection of HCC.
Collapse
Affiliation(s)
- Jianhui Zhu
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Elisa Warner
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Neehar D. Parikh
- Department of Internal Medicine, The University of Michigan, Ann Arbor 48109, Michigan
| | - David M. Lubman
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| |
Collapse
|
|
44
|
Wang M, Zhu J, Lubman DM, Gao C. Aberrant glycosylation and cancer biomarker discovery: a promising and thorny journey. Clin Chem Lab Med 2019; 57:407-416. [PMID: 30138110 PMCID: PMC6785348 DOI: 10.1515/cclm-2018-0379] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 07/15/2018] [Indexed: 12/12/2022]
Abstract
Glycosylation is among the most important post-translational modifications for proteins and is of intrinsic complex character compared with DNAs and naked proteins. Indeed, over 50%-70% of proteins in circulation are glycosylated, and the "sweet attachments" have versatile structural and functional implications. Both the configuration and composition of the attached glycans affect the biological activities of consensus proteins significantly. Glycosylation is generated by complex biosynthetic pathways comprising hundreds of glycosyltransferases, glycosidases, transcriptional factors, transporters and the protein backbone. In addition, lack of direct genetic templates and glyco-specific antibodies such as those commonly used in DNA amplification and protein capture makes research on glycans and glycoproteins even more difficult, thus resulting in sparse knowledge on the pathophysiological implications of glycosylation. Fortunately, cutting-edge technologies have afforded new opportunities and approaches for investigating cancer-related glycosylation. Thus, glycans as well as aberrantly glycosylated protein-based cancer biomarkers have been increasingly recognized. This mini-review highlights the most recent developments in glyco-biomarker studies in an effort to discover clinically relevant cancer biomarkers using advanced analytical methodologies such as mass spectrometry, high-performance liquid chromatographic/ultra-performance liquid chromatography, capillary electrophoresis, and lectin-based technologies. Recent clinical-centered glycobiological studies focused on determining the regulatory mechanisms and the relation with diagnostics, prognostics and even therapeutics are also summarized. These studies indicate that glycomics is a treasure waiting to be mined where the growth of cancer-related glycomics and glycoproteomics is the next great challenge after genomics and proteomics.
Collapse
Affiliation(s)
- Mengmeng Wang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Chunfang Gao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
| |
Collapse
|
|
45
|
Bharali D, Banerjee BD, Bharadwaj M, Husain SA, Kar P. Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: A protein-based hepatocellular carcinoma-associated study. Indian J Med Res 2018; 147:361-368. [PMID: 29998871 PMCID: PMC6057253 DOI: 10.4103/ijmr.ijmr_1358_16] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background & objectives: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The objective of this study was to find out the differential expression of apolipoproteins (ApoAI and ApoAIV) in HCC and cases of liver cirrhosis and chronic hepatitis (controls) without HCC and to compare ApoAI and ApoAIV expression with alpha-foetoprotein (AFP), the conventional marker in HCC. Methods: Fifty patients with HCC and 50 controls comprising patients with liver cirrhosis (n=25) and chronic hepatitis (n=25) without HCC were included in this study. Total proteins were precipitated using acetone precipitation method followed by albumin and IgG depletion of precipitated protein using depletion kit. Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expression changes of ApoAI and ApoAIV were confirmed by western blotting using specific primary and secondary polyclonal antibodies followed by densitometric protein semi-quantitative estimation. ApoAI, ApoAIV and AFP were measured in the plasma samples by ELISA method. Results: Semi-quantitative densitometric image analysis of the western blot images and the comparison between HCC patients with those without HCC (control) revealed differential expression of ApoAI and ApoAIV. Levels of ApoAI were significantly higher in patients with HCC compared to controls without HCC (0.279±0.216 vs 0.171±0.091 and 0.199±0.014; P <0.001). Levels of ApoAIV were significantly lower in patients of HCC compared to controls without HCC (0.119±0.061 vs 0.208±0.07 and 0.171±0.16; P <0.01). ELISA assays of apolipoproteins (ApoAI and ApoAIV) revealed similar results of expression of ApoAI and ApoAIV as detected in western blotting densitometric image analysis. Interpretation & conclusions: Increased expression of ApoAI and decreased expression of ApoAIV in HCC patients compared to controls without HCC revealed the abnormalities in HCC. These molecules need to be studied further for their use as potential biomarkers in the future diagnostic tools along with other conventional biomarkers for screening of HCC cases. It needs further analysis in higher number of patient population.
Collapse
Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Basu Dev Banerjee
- Department of Biochemistry, University College of Medical Sciences, Delhi, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, ICMR-National Institute of Cancer Prevention & Research, Noida, India
| | - Syed Akhtar Husain
- Department of Biosciences, Jamia Milia Islamia University, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| |
Collapse
|
|
46
|
Abdel-Hamid M, Nada OH, Ellakwa DES, Ahmed LK. Role of Myeloperoxidase in hepatitis C virus related hepatocellular carcinoma. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
|
|
47
|
Jiang H, Zhang L, Zhang Y, Xie L, Wang Y, Lu H. HST-MRM-MS: A Novel High-Sample-Throughput Multiple Reaction Monitoring Mass Spectrometric Method for Multiplex Absolute Quantitation of Hepatocellular Carcinoma Serum Biomarker. J Proteome Res 2018; 18:469-477. [PMID: 30346787 DOI: 10.1021/acs.jproteome.8b00790] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Absolute quantification of clinical biomarkers by mass spectrometry (MS) has been challenged due to low sample-throughput of current multiple reaction monitoring (MRM) methods. For this problem to be overcome, in this work, a novel high-sample-throughput multiple reaction monitoring mass spectrometric (HST-MRM-MS) quantification approach is developed to achieve simultaneous quantification of 24 samples. Briefly, triplex dimethyl reagents (L, M, and H) and eight-plex iTRAQ reagents were used to label the N- and C-termini of the Lys C-digested peptides, respectively. The triplex dimethyl labeling produces three coelute peaks in MRM traces, and the iTRAQ labeling produces eight peaks in MS2, resulting in 24 (3×8) channels in a single experiment. HST-MRM-MS has shown good accuracy ( R2 > 0.98 for absolute quantification), reproducibility (RSD < 15%), and linearity (2-3 orders of magnitude). Moreover, the novel method has been successfully applied in quantifying serum biomarkers in hepatocellular carcinoma (HCC)-related serum samples. In conclusion, HST-MRM-MS is an accurate, high-sample-throughput, and broadly applicable MS-based absolute quantification method.
Collapse
|
|
48
|
Silva MLS. Lectin-based biosensors as analytical tools for clinical oncology. Cancer Lett 2018; 436:63-74. [PMID: 30125611 DOI: 10.1016/j.canlet.2018.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/07/2018] [Accepted: 08/08/2018] [Indexed: 12/17/2022]
Abstract
The review focus on the use of lectin-based biosensors in the oncology field, and ponders the potentialities of using these devices as analytical tools to monitor the levels of cancer glycobiomarkers in biological fluids, helping in the diagnosis, prognosis and treatment assessment. Several examples of lectin-based biosensors directed for cancer biomarkers are described and discussed, and their potential application in the clinic is considered, taking into account their analytical features, advantages and performance in sample analysis. Technical and practical aspects in the construction process, which are specific for lectin biosensors, are debated, as well as the requirements in sample collection and processing, and biosensor validation. Today's challenges for real implementation of these devices in the clinic are presented, along with the future trends in the field.
Collapse
Affiliation(s)
- M Luísa S Silva
- Centre of Chemical Research, Autonomous University of Hidalgo State, Carr. Pachuca-Tulancingo Km 4.5, 42076, Pachuca, Hidalgo, Mexico; LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy of the University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
| |
Collapse
|
|
49
|
Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, Heimbach JK. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018; 68:723-750. [PMID: 29624699 DOI: 10.1002/hep.29913] [Citation(s) in RCA: 3179] [Impact Index Per Article: 454.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 03/13/2018] [Indexed: 12/11/2022]
|
|
50
|
Kotha S, Neong S, Patel K. Serum biomarkers for diagnosis and monitoring viral hepatitis and hepatocellular carcinoma. Expert Rev Mol Diagn 2018; 18:713-722. [PMID: 30019978 DOI: 10.1080/14737159.2018.1496020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Chronic liver disease due to viral hepatitis continues to be a major global health concern. Timely diagnosis and treatment will prevent cirrhosis, risk of hepatocellular carcinoma (HCC), and requirement for liver transplantation. Numerous serum biomarkers are available for viral hepatitis that are helpful in diagnosis, measuring severity, progression of disease, evaluating the best therapeutic options, and monitoring antiviral treatment response. Determining the clinical use of available diagnostic tests can be challenging for the health care provider. Areas covered: This review article attempts to summarize the established and emerging serological markers for diagnosis and managing viral hepatitis. The literature search was performed in February 2018 and included MEDLINE and Embase databases for recent relevant literature on biomarkers for viral hepatitis. Expert Commentary: Despite the discovery of several candidate biomarkers, translating these to clinical practice in viral hepatitis and HCC remains challenging. While limited availability of the new biomarkers in prevalent geographic areas and significant cost remain major obstacles, there have been exciting developments in this field. Understanding the detection limits and sensitivity of these markers and translating them into clinical use is important in management of viral hepatitis and complications of liver disease such as cirrhosis and hepatocellular cancer.
Collapse
Affiliation(s)
- Sreelakshmi Kotha
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
| | - ShuetFong Neong
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
| | - Keyur Patel
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
| |
Collapse
|