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Spiers J, Li W, Aravinthan AD, Bannaga A, Caddick K, Culver EL, Faulkes RE, Gordon V, Hussain Y, Miller H, Merry J, Saad M, Sheth A, Shah T, Shetty S, Srivastava A, Subhani M, Tahir MN, Than NN, Unitt E, Alazawi W. Current Surveillance Strategy Is Less Effective for Detecting Early-Stage Hepatocellular Carcinoma in Patients with Non-Viral and Non-Cirrhotic Liver Disease. Liver Cancer 2025:1-14. [PMID: 40337094 PMCID: PMC12055015 DOI: 10.1159/000542805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 11/21/2024] [Indexed: 05/09/2025] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Current international guidelines recommend 6-monthly ultrasound surveillance in all patients with cirrhosis and those with hepatitis B virus-related risk factors to detect early-stage HCC. However, it is unknown whether the benefits of surveillance are comparable across patient groups and underlying disease-related factors. We aimed to evaluate patient- and disease-related factors associated with HCC stage at diagnosis and survival in an ethnically diverse UK population. Methods This was a multicentre retrospective observational study including patients with newly diagnosed HCC between 2007 and 2020 from six UK centres. Cox proportional-hazards regression and multivariate logistic regression models were used. Results Overall, 1,780 HCC patients comprising 20.9% with ArLD, 29.7% with NAFLD, and 31.0% with viral hepatitis were analysed. Surveillance was associated with improved survival in patients with viral hepatitis but not in patients with ArLD and NAFLD. Surveillance was also associated with early-stage disease (BCLC stage 0 or A) at presentation in viral hepatitis but not in patients with ArLD. Females with ArLD were 2.5-fold more likely to present with early-stage HCC than males. Patients with NAFLD were more likely to develop HCC in the absence of cirrhosis. Type 2 diabetes was not associated with mortality, but metformin use did show survival benefit. Patients of white ethnicity had improved survival and were less likely to present with late-stage HCC compared to other ethnicities. Conclusions HCC surveillance as currently delivered was less effective for detecting early-stage HCC in patients with non-viral and non-cirrhotic liver disease. Gender and ethnicity influences stage at presentation and outcomes. HCC surveillance strategies are needed to refine risk stratification particularly in patients with NAFLD or without cirrhosis.
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Affiliation(s)
- Jessica Spiers
- Barts Liver Centre, Blizard Institute, Queen Mary Unversity of London, London, UK
| | - Wenhao Li
- Barts Liver Centre, Blizard Institute, Queen Mary Unversity of London, London, UK
| | - Aloysious D. Aravinthan
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | - Ayman Bannaga
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
| | | | - Emma L. Culver
- Translational Gastroenterology Unit, John Radcliffe Hospital, and Oxford NIHR and BRC Oxford, Oxford, UK
| | | | - Victoria Gordon
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Yaqza Hussain
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Hamish Miller
- Barts Liver Centre, Blizard Institute, Queen Mary Unversity of London, London, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, and Oxford NIHR and BRC Oxford, Oxford, UK
| | - Jenny Merry
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Muhammad Saad
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Abhishek Sheth
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | - Tahir Shah
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
| | | | | | - Mohsan Subhani
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | | | - Nwe Ni Than
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Esther Unitt
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - William Alazawi
- Barts Liver Centre, Blizard Institute, Queen Mary Unversity of London, London, UK
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Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 2023; 5:100811. [PMID: 37575883 PMCID: PMC10413159 DOI: 10.1016/j.jhepr.2023.100811] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 08/15/2023] Open
Abstract
Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.
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Affiliation(s)
- Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Eduardo H. Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Camilo J. Llamoza-Torres
- Department of Hepatology, Virgen de la Arrixaca University Hospital, Murcia, 30120, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Esteban N. Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
- WELBIO Department, WEL Research Institute, Avenue Pasteur 6, Wavre, 1300, Belgium
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Cigrovski Berkovic M, Giovanardi F, Mrzljak A, Lai Q. Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis. World J Diabetes 2023; 14:1289-1300. [PMID: 37664473 PMCID: PMC10473950 DOI: 10.4239/wjd.v14.i8.1289] [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: 02/27/2023] [Revised: 04/24/2023] [Accepted: 05/16/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth. AIM To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients. METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted. RESULTS A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31). CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.
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Affiliation(s)
- Maja Cigrovski Berkovic
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, Zagreb 10000, Croatia
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
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Yang J, Yang H, Cao L, Yin Y, Shen Y, Zhu W. Prognostic value of metformin in cancers: An updated meta-analysis based on 80 cohort studies. Medicine (Baltimore) 2022; 101:e31799. [PMID: 36626437 PMCID: PMC9750609 DOI: 10.1097/md.0000000000031799] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Experiments have shown that metformin can inhibit cancer cell growth, but clinical observations have been inconsistent, so we pooled the currently available data to evaluate the impact of metformin on cancer survival and progression. METHODS PubMed, web of science, Embase, and Cochrane databases were searched. Pooled hazard ratios (HRs) were identified using a random-effects model to estimate the strength of the association between metformin and survival and progression in cancer patients. RESULTS We incorporated 80 articles published from all databases which satisfied the inclusion criterion. It showed that metformin was associated with better overall survival (hazard ratio [HR] = 0. 81; 95% confidence interval [CI]: [0.77-0.85]) and cancer-specific survival (HR = 0.79; 95% CI: [0.73-0.86]), and metformin was associated with progression-free survival (HR = 0.76; 95% CI: [0.66-0.87]). In patients with diabetes mellitus, the HR of overall survival was 0.79(95% CI: [0.75-0.83]), progression-free survival was 0.72(95% CI: [0.60-0.85]), and the cancer-specific survival was 0.76(95% CI: [0.68-0.86]). It was proposed that metformin can improve the prognosis of cancer patients with diabetes mellitus. CONCLUSION Based on cohort studies, metformin therapy has potential survival benefits for patients with malignancy, especially with the greatest benefits seen in breast cancer on overall survival, progression-free survival, and cancer-specific survival. And metformin also showed potential benefits in cancer-specific survival in colorectal and prostate cancer.
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Affiliation(s)
- Jing Yang
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu Province, P.R. China
| | - Hang Yang
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu Province, P.R. China
| | - Ling Cao
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu Province, P.R. China
| | - Yuzhen Yin
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu Province, P.R. China
| | - Ying Shen
- Department of Endocrinology, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu Province, P.R. China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
- * Correspondence: Wei Zhu, Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China (e-mail: )
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Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology 2022; 76:1880-1897. [PMID: 35239194 PMCID: PMC9790535 DOI: 10.1002/hep.32439] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Ariel Jaffe
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Rachel Perry
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Section of EndocrinologyDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Mario Strazzabosco
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
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Gales L, Forsea L, Mitrea D, Stefanica I, Stanculescu I, Mitrica R, Georgescu M, Trifanescu O, Anghel R, Serbanescu L. Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy. Medicina (B Aires) 2022; 58:medicina58091239. [PMID: 36143915 PMCID: PMC9503803 DOI: 10.3390/medicina58091239] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/29/2022] [Accepted: 09/02/2022] [Indexed: 11/25/2022] Open
Abstract
Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients’ daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient’s daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.
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Affiliation(s)
- Laurentia Gales
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Oncology, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Leyla Forsea
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Mitrea
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Irina Stefanica
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Irina Stanculescu
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Radu Mitrica
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
- Correspondence: ; Tel.: +40-741-964-311
| | - Mihai Georgescu
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Oana Trifanescu
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Rodica Anghel
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Luiza Serbanescu
- Department of Oncology, “Carol Davila” University of Medicine & Pharmacy, 022328 Bucharest, Romania
- Department of Radiotherapy, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
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Metformin administration is associated with enhanced response to transarterial chemoembolization for hepatocellular carcinoma in type 2 diabetes patients. Sci Rep 2022; 12:14482. [PMID: 36008432 PMCID: PMC9411109 DOI: 10.1038/s41598-022-18341-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 08/09/2022] [Indexed: 12/09/2022] Open
Abstract
Transarterial chemoembolization (TACE) is often used as a locoregional therapy for early hepatocellular carcinoma (HCC) when local ablation or resection are not feasible, but incomplete response and recurrence are commonly observed. In this study, we sought to determine the association between metformin administration and TACE outcomes for single nodular HCC in patients with type 2 diabetes mellitus (T2DM). The retrospective cohort analysis included 164 T2DM patients with single nodular HCC who underwent TACE as an initial treatment, and 91 were exposed to metformin before and after TACE. Propensity score (PS) matching was used to balance covariates. Logistic regression analysis was used to determine the predictors of tumor response after TACE, and Cox regression analysis assessed independent predictors of local tumor recurrence (LTR) in patients with complete response after TACE. Metformin use was associated with significantly higher objective response rate (ORR) in the overall and PS-matched cohort (79.1% vs. 60.3 and 78.7% vs. 57.5%; p = 0.008 and p = 0.029, respectively). Logistic regression analysis showed that metformin use was an independent predictor of ORR in all and PS-matched patients (odds ratio = 2.65 and 3.06; p = 0.016 and 0.034, respectively). Cox regression analysis showed metformin administration was an independent predictor for lower LTR in all and PS-matched patients (hazard ratio = 0.28 and 0.27; p = 0.001 and 0.007, respectively). Metformin administration is associated with better initial response and lower local recurrence after TACE for single nodular HCC in T2DM.
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Cao JZ, Wang ZG, Yu J, Tao YP, Yang Y, Liu H, Zhou WP, Lu J, Huang Q. Antidiabetic treatment improves prognosis after radical resection in hepatocellular carcinoma patients with diabetes mellitus: a retrospective cohort study from 2000 to 2013. J Gastrointest Oncol 2022; 13:1330-1339. [PMID: 35837203 PMCID: PMC9274028 DOI: 10.21037/jgo-22-478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/14/2022] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND It remains unclear whether diabetic medications, such as metformin and insulin, affect the post-liver resection prognosis of hepatocellular carcinoma (HCC) patients complicated with diabetes mellitus (DM). This study try to find out the prognostic factors in HCC patients with DM and provide a better antidiabetic therapy after liver resection. METHODS Patients presenting with HCC complicated with DM undergoing liver resection were enrolled in this study. They were examined and followed up every 3-6 months after surgery. Patients were divided into the antidiabetic treatment group and no antidiabetic treatment group according to whether they received medications for diabetes or not. Then patients in the antidiabetic treatment group were further divided into insulin group, metformin group, insulin plus metformin group and others group, according to the medications they received. Overall survival (OS) and recurrence-free survival (RFS) were compared among two groups and four subgoups. Comparative and multivariate analyses were performed to investigate the effects of DM medication on the prognosis of these HCC patients, using Cox proportional hazards model. RESULTS The 1-, 3-, 5-, and 7-year OS rates for the antidiabetic treatment group were 87.5%, 75.5%, 48.7%, and 29.1%, respectively, and for the no antidiabetic treatment group, the OS rates were 85.4%, 57.7%, 33.6%, and 19.1%, respectively (P=0.007). The 1-, 3-, 5-, 7-year RFS rates for the antidiabetic treatment group were 76.4%, 53.5%, 28.5%, and 17.5%, respectively, and for the no antidiabetic treatment group, the RFS rates were 69.5%, 32.5%, 16.5%, and 10.7%, respectively (P=0.001). In subgroup analysis, There was no significant difference in either RFS (P=0.934) nor OS (P=0.412) among the different types of antidiabetic treatment regimens. Cox proportional hazard regression analysis revealed that tumor size (HR: 1.048), tumor number (HR: 1.626), vascular invasion (HR: 2.074, P=0.003), satellite tumor (HR: 1.592), Edmondson classification (HR: 1.468) and antidiabetic treatment (HR: 0.722) were independent prognostic factors of DFS, while tumor size (HR: 1.048), tumor number (HR: 1.779), vascular invasion (HR: 2.545), Edmondson classification (HR: 1.596) and antidiabetic treatment (HR: 0.713) were independent prognostic factors of OS. CONCLUSIONS For HCC patients with DM, antidiabetic treatment should be recommended aggressively in order to improve the surgical outcome, regardless of which antidiabetic drugs are used.
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Affiliation(s)
- Jing-Zhu Cao
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Guang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Ping Tao
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
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Mrzljak A, Cigrovski Berković M, Giovanardi F, Lai Q. The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis. Croat Med J 2022; 63:176-186. [PMID: 35505651 PMCID: PMC9086813 DOI: 10.3325/cmj.2022.63.176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/23/2021] [Indexed: 11/05/2022] Open
Abstract
AIM To evaluate the effect of diabetes mellitus type 2 (T2DM) on the outcomes after treatment of hepatocellular carcinoma (HCC). METHODS PubMed and Cochrane Central Register of Controlled Trials Databases were systematically searched. Three HCC clinical outcomes were explored: death, progressive disease after locoregional therapies, and recurrence. Sub-analysis was performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between T2DM and non-T2DM groups. RESULTS A total of 27 studies were analyzed. Overall, 85.2% of articles were from Asia. T2MD was associated with an increased risk of death (OR 3.60; 95%CI 2.18-5.95; P<0.001), irrespective of the treatment approach: curative (OR 1.30 95%CI 1.09-1.54; P=0.003) or non-curative (OR 1.05; 95%CI 1.00-1.10; P=0.045), increased HCC recurrence (OR 1.30; 95%CI 1.03-1.63; P=0.03), and increased disease progressiveness (OR 1.24; 95%CI 1.09-1.41; P=0.001). CONCLUSIONS Current data provide strong evidence that T2DM unfavorably affects HCC progression and recurrence, and patients' survival after treatment, irrespective of the approach used.
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Affiliation(s)
| | - Maja Cigrovski Berković
- Maja Cigrovski Berković, Department of Endocrinology, Diabetes, Metabolism and Clinical Pharmacology, University Hospital Dubrava, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia,
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Chen ML, Wu CX, Zhang JB, Zhang H, Sun YD, Tian SL, Han JJ. Transarterial chemoembolization combined with metformin improves the prognosis of hepatocellular carcinoma patients with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:996228. [PMID: 36187118 PMCID: PMC9520252 DOI: 10.3389/fendo.2022.996228] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The study aims to investigate the effect of metformin on Hepatocellular carcinoma (HCC) patients with type 2 diabetes mellitus (T2DM) who received transarterial chemoembolization (TACE) for the first time. METHODS From January 2016 to December 2019, T2DM patients diagnosed with HCC in Shandong Cancer Hospital and treated with TACE were included in this retrospective study. Overall survival (OS) and Progression-free survival (PFS) were compared between patients treated with metformin and other antidiabetics. Univariate and multivariate Cox regression models were used to evaluate the independent risk factors associated with OS and PFS. And sub-analysis was performed to investigate whether metformin could give a survival advantage in each Barcelona Clinic Liver Cancer (BCLC) stage of HCC. Propensity score matched (PSM) analyses based on patient and tumor characteristics were also conducted. RESULTS A total of 123 HCC patients with T2DM underwent TACE, of which 50 (40.65%) received treatment with metformin. For the whole cohort, the median OS (42 vs 32 months, p=0.054) and PFS (12 vs 7 months, P=0.0016) were longer in the metformin group than that in the non-metformin group. Multi-analysis revealed that BCLC stage, BMI (Body Mass Index), and metformin use were independent predictors of OS. Metformin use was independently associated with recurrence. After PSM, 39 matched pairs were identified. The use of metformin was associated with a numerically longer m OS (43 vs 35 months, P=0.183) than the use of other anti-diabetics. And the difference in median PFS (13 vs 7 months, p=0.018) between the metformin group and non-metformin group remained significant. CONCLUSION The combination of transarterial chemoembolization and metformin may be associated with better OS and PFS in HCC patients with T2DM.
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Affiliation(s)
- Miao-Ling Chen
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chun-Xue Wu
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jian-Bo Zhang
- Pathology Department, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Hao Zhang
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yuan-Dong Sun
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shi-Lin Tian
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jian-Jun Han
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Jian-Jun Han, ;
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Harati R, Vandamme M, Blanchet B, Bardin C, Praz F, Hamoudi RA, Desbois-Mouthon C. Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells. Mol Pharmacol 2021; 100:32-45. [PMID: 33990407 DOI: 10.1124/molpharm.120.000223] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/09/2021] [Indexed: 01/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.
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Affiliation(s)
- Rania Harati
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Marc Vandamme
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Benoit Blanchet
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christophe Bardin
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Françoise Praz
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Rifat Akram Hamoudi
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christèle Desbois-Mouthon
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
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El Shorbagy S, abuTaleb F, Labib HA, Ebian H, Harb OA, Mohammed MS, Rashied HA, Elbana KA, Haggag R. Prognostic Significance of VEGF and HIF-1 α in Hepatocellular Carcinoma Patients Receiving Sorafenib Versus Metformin Sorafenib Combination. J Gastrointest Cancer 2021; 52:269-279. [PMID: 32212089 DOI: 10.1007/s12029-020-00389-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major health problem. HCC burden has been increasing in Egypt in the past 10 years. Most HCC cases are diagnosed at an advanced stage with limited treatment options. Sorafenib is the standard therapy for advanced HCC, but the effectiveness is not satisfied. Metformin may decrease the risk of HCC development in diabetic patients, reduces tumor invasion, and augments sensitivity to sorafenib; however, safety and efficacy of combined treatment are still unclear. As HCC is characterized by high vascularity, and vascular endothelial growth factor (VEGF) plays an important role in vascularization, many studies questioned if VEGF and HIF-1 α could offer information about HCC response to sorafenib. We conducted this study to assess the benefits from adding metformin to HCC treatment, and appraise the role of VEGF and HIF-1 α in HCC prognosis. METHOD This was a prospective, randomized study in which 80 advanced measurable patients consecutively treated with sorafenib plus metformin (arm A) or sorafenib alone (arm B), prognostic value of plasma, and tissue levels of VEGF and HIF-1 α were evaluated. RESULTS We enrolled 61 men and 19 women with a median age of 60 years (range 49-68 years). Fifty-seven patients had Child-Pugh A while 23 had early B, the most common etiology of liver disease was hepatitis C (86%). Sixty percent of patients were diabetic. No significant difference was detected between arm A and arm B regarding response to treatment (p = 0.5), time to disease progression (p = 0.3), or overall survival (p = 0.6). Low VEGF and HIF-1 α plasma levels were significantly associated with better treatment response (p < 0.001 for both), and higher OS (p < 0.001). Patients with high expressions of VEGF and HIF in HCC tissue had significantly poor treatment outcome (p < 0.001, p = 0.03, respectively), and poor OS (p < 0.001, p < 0.001, respectively). CONCLUSIONS No superior efficacy of adding metformin to sorafenib in HCC treatment. VEGF and HIF-1 α had promising prognostic value in HCC.
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Affiliation(s)
- Shereen El Shorbagy
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Fouad abuTaleb
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Hany A Labib
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Huda Ebian
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ola A Harb
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mona Saeed Mohammed
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Khaled A Elbana
- Internal Medicine department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Rasha Haggag
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
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Cho WR, Wang CC, Tsai MY, Chou CK, Liu YW, Wu YJ, Lin MT, Chen KD, Chuang CH, Huang PY, Hu TH, Tsai MC. Impact of metformin use on the recurrence of hepatocellular carcinoma after initial liver resection in diabetic patients. PLoS One 2021; 16:e0247231. [PMID: 33661912 PMCID: PMC7932176 DOI: 10.1371/journal.pone.0247231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
Background Metformin is proposed to have chemopreventive effect of various cancer currently. However, the anti-cancer effect of metformin for diabetic patients with hepatocellular carcinoma (HCC) undergoing liver resection remains unclear. The aim of our cohort study was to assess whether metformin influence the recurrence of HCC. Methods We retrospectively enrolled 857 HCC patients who received primary resection from April 2001 to June 2016. 222 patients were diagnosed with diabetes mellitus (DM) from medical record. Factors influence the overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis. Results During the follow-up period (mean, 75 months), 471 (54.9%) patients experienced recurrence, and 158 (18.4%) patients died. Multivariate analysis revealed that DM (p = 0.015), elevated AST (p = 0.006), hypoalbuminemia (p = 0.003), tumor number (p = 0.001), tumor size (p < 0.001), vascular invasion (p <0.001), high Ishak fibrosis score (p <0.001), hepatitis B (p = 0.014), hepatitis C (p = 0.001) were independent predictors for RFS. In diabetic patients, only HbA1c>9% (p = 0.033), hypoalbuminemia (p = 0.030) and vascular invasion (p = 0.001) were independent risk factors for HCC recurrence; but the metformin use revealed no significance on recurrence. DM is a risk factor of HCC recurrence after resection. Adequate DM control can reduce the recurrence of HCC. However, the use of metformin does not reduce the risk of HCC recurrence in diabetic patient after initial resection. Hence, metformin may not have protective influences on HCC recurrence in diabetic patients who undergo initial liver resection.
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Affiliation(s)
- Wei-Ru Cho
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University Medical College, Kaohsiung, Taiwan
| | - Meng-Yun Tsai
- Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chen-Kai Chou
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yueh-Wei Liu
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University Medical College, Kaohsiung, Taiwan
| | - Yi-Ju Wu
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University Medical College, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuang-Den Chen
- Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | - Pao-Yuan Huang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan
- * E-mail:
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Tangjarusritaratorn T, Tangjittipokin W, Kunavisarut T. Incidence and Survival of Hepatocellular Carcinoma in Type 2 Diabetes Patients with Cirrhosis Who Were Treated with and without Metformin. Diabetes Metab Syndr Obes 2021; 14:1563-1574. [PMID: 33859487 PMCID: PMC8043797 DOI: 10.2147/dmso.s295753] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/12/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To evaluate metformin's benefit on the incidence and survival of hepatocellular carcinoma (HCC) in cirrhosis with type 2 diabetes mellitus (T2DM) patients. PATIENTS AND METHODS We conducted a retrospective study from 2006 to 2019. The patients were assigned to metformin exposure if they administered metformin at least 3 months after diagnosis of cirrhosis. The outcomes were incidence and survival of HCC in T2DM with cirrhosis treated with metformin compared with those who were not treated with metformin. For the incidence of HCC, the follow-up time was 5 years after cirrhosis was diagnosed. For the survival of HCC, we censored for vital status in June 2019. RESULTS Of 1061 patients, the patients were divided into 719 patients with metformin exposure and 342 in metformin non-exposure. In metformin exposure, 125 patients (17.4%) developed HCC. In metformin non-exposure, 128 patients (37.4%) developed HCC. Metformin exposure had a significantly lower risk of developing HCC in multivariate analysis HR 0.48 (0.36-0.61); P<0.001. For the survival of HCC, 327 patients were recruited. One-hundred and sixty-two patients were in metformin exposure and 165 patients were in metformin non-exposure. Sixty patients (37%) in metformin exposure died, while 84 patients (50.9%) in metformin non-exposure died. The median survival of metformin exposure and metformin non-exposure were 6.9 years and 3.88 years, respectively; P=0.003. In univariate analysis, the metformin exposure was significantly associated with better survival than in the non-exposure group, HR 0.63 (0.45-0.88); P=0.006. No significant difference was observed in multivariate analysis between two groups, HR 1.07 (0.74-1.54); P=0.72. CONCLUSION Metformin exposure was associated with a lower incidence of HCC in cirrhosis with T2DM patients and seemed to extend survival. Continuing metformin in patients with cirrhosis with T2DM should be considered if there was no contraindication.
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Affiliation(s)
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Siriraj Center of Research Excellence in Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tada Kunavisarut
- Division of Endocrinology & Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Correspondence: Tada Kunavisarut Division of Endocrinology & Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok, 10700, ThailandTel +66 2-419-7799Fax +66 2-419-7792 Email
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Survival advantage associated with metformin usage in hepatocellular carcinoma patients with diabetes mellitus receiving radical resection: a propensity score matching analysis. Eur J Gastroenterol Hepatol 2020; 32:1030-1035. [PMID: 31764404 PMCID: PMC7337117 DOI: 10.1097/meg.0000000000001610] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Metformin is associated with improved survival among hepatocellular carcinoma (HCC) patients with diabetes mellitus. However, the role of metformin in the survival of hepatitis B virus (HBV)-related HCC patients with diabetes mellitus after radical resection is unclear, so this study aimed to assess the effects of metformin on the clinical outcomes of patients who received radical resection for HCC. PATIENTS AND METHODS A total of 250 HCC patients (30-78 years old) diagnosed with diabetes mellitus were selected between 2000 and 2013 from the First Affiliated Hospital of Nanchang University and the Eastern Hepatobiliary Surgery Hospital in China. Patients were divided into the metformin group (n = 66) and the nonmetformin group (n = 184). A propensity score matching analysis was performed to evaluate the effect of metformin in patients receiving radical resection for HCC. RESULTS In the propensity score-matched cohort (n = 176), the overall survival (OS) in the metformin group at 1, 3, and 5 years was significantly higher than in the nonmetformin group (P = 0.002), and a similar treatment effect was observed for disease-free survival (DFS) (P = 0.030). The adjusted Cox proportional hazards model showed that metformin usage significantly improved OS [hazard ratio: 0.558, 95% confidence interval (CI): 0.385-0.810]. CONCLUSIONS Metformin is associated with satisfactory clinical outcomes among HBV-related HCC patients with diabetes mellitus after radical resection. The use of metformin could significantly improve the OS and reduce the risk of HCC recurrence in patients after radical resection. A prospective controlled study is recommended to verify the metformin effect and explore its possible mechanisms.
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Zhou J, Ke Y, Lei X, Wu T, Li Y, Bao T, Tang H, Zhang C, Wu X, Wang G, Li J, Zhang H, Ni F, Ye Z, Wang L. Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes. Ann Hepatol 2020; 19:320-328. [PMID: 31980358 DOI: 10.1016/j.aohep.2019.11.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 10/30/2019] [Accepted: 11/14/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION This study aimed to compare the therapeutic efficacy of metformin and other anti-hyperglycemic agents in hepatocellular carcinoma (HCC) patients with type 2 diabetes (T2D). MATERIALS A systematic electronic search on keywords including HCC and different anti-hyperglycemic agents was performed through electronic databases including Medline and EMBASE. The primary outcome was the overall survival (OS). The secondary outcomes were the recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS Six retrospective cohort studies were included for analysis: Four studies with curative treatment for HCC (618 patients with metformin and 532 patients with other anti-hyperglycemic agents) and two studies with non-curative treatment for HCC (92 patients with metformin and 57 patients with other anti-hyperglycemic agents). Treatment with metformin was associated with significantly longer OS (OR1yr=2.62, 95%CI: 1.76-3.90; OR3yr=3.14, 95%CI: 2.33-4.24; OR5yr=3.31, 95%CI: 2.39-4.59, all P<0.00001) and RFS (OR1yr=2.52, 95%CI: 1.84-3.44; OR3yr=2.87, 95%CI: 2.15-3.84; all P<0.00001; and OR5yr=2.26, 95%CI: 0.94-5.45, P=0.07) rates vs. those of other anti-hyperglycemic agents after curative therapies for HCC. However, both of the two studies reported that following non-curative HCC treatment, there were no significant differences in the OS and PFS rates between the metformin and non-metformin groups (I2>50%). CONCLUSIONS Metformin significantly prolonged the survival of HCC patients with T2D after the curative treatment of HCC. However, the efficacy of metformin needs to be further determined after non-curative therapies for HCC patients with T2D.
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Affiliation(s)
- Jian Zhou
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Yang Ke
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Xuefen Lei
- Department of Medical Oncology, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Tiangen Wu
- Department of Gastroenterological Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuehua Li
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Tianhao Bao
- Mental Health Center of Kunming Medical University, Kunming, Yunnan, China
| | - Haoran Tang
- Department of Gastroenterological Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Cheng Zhang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China; Department of Hepatobiliary Surgery, the Sixth People's Hospital of Chengdu, Chengdu, Sichuan, China
| | - Xuesong Wu
- Department of Gastroenterological Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ge Wang
- Department of Gastroenterological Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jinze Li
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Heng Zhang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Fan Ni
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Zhengchen Ye
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; The Yunnan Provincial Clinical Center for Hepato-biliary-pancreatic Diseases, Kunming, Yunnan, China.
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Antwi SOP, Li Z, Mody K, Roberts LR, Patel T. Independent and Joint Use of Statins and Metformin by Elderly Patients With Diabetes and Overall Survival Following HCC Diagnosis. J Clin Gastroenterol 2020; 54:468-476. [PMID: 32271517 PMCID: PMC7150664 DOI: 10.1097/mcg.0000000000001182] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
GOAL To investigate associations of prediagnosis and postdiagnosis use of statins and metformin on overall survival of patients with diabetes who later developed HCC. BACKGROUND Statins and metformin have received considerable interest as potential chemopreventive agents against hepatocellular carcinoma (HCC) development in individuals with type 2 diabetes mellitus (T2DM); however, their impact on overall survival of patients with T2DM who later develop HCC (diabetic HCC patients) is unclear. STUDY Data on 2499 elderly diabetic HCC patients obtained from the SEER-Medicare program (2009 to 2013) were analyzed. Patients were categorized based on use of statins only, metformin only, both, or neither (reference for all comparisons). The patients were further categorized based on: (1) metformin dose: ≤1500 or >1500 mg/d; (2) statins functional form: hydrophilic (pravastatin and rosuvastatin) or lipophilic (atorvastatin, fluvastatin, lovastatin, and simvastatin); (3) statins potency: high (atorvastatin, rosuvastatin, and simvastatin) or low (fluvastatin, lovastatin, and pravastatin); and (4) individual statins type. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. RESULTS Prediagnosis use of metformin dose ≤1500 mg/d was associated with lower risk of death after HCC diagnosis in patients with T2DM (HR, 0.72; 95% CI, 0.58-0.91), adjusting for postdiagnosis metformin dose, diabetes severity, Charlson comorbidity index, tumor characteristics, and other relevant factors. No association was found for prediagnosis metformin dose >1500 mg/d or postdiagnosis metformin use. Further, no association was found for either prediagnosis or postdiagnosis statins use. CONCLUSIONS Prediagnosis use of metformin dose ≤1500 mg/d is associated with longer overall survival of elderly diabetic HCC patients.
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Affiliation(s)
| | - Zhuo Li
- Health Sciences Research, Mayo Clinic, Jacksonville, FL
| | - Kabir Mody
- Medical Oncology, Mayo Clinic, Jacksonville, FL
| | | | - Tushar Patel
- Transplant Hepatology, Mayo Clinic, Jacksonville, FL
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18
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Jiang X, Tan HY, Teng S, Chan YT, Wang D, Wang N. The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:647. [PMID: 31083406 PMCID: PMC6562911 DOI: 10.3390/cancers11050647] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy.
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Affiliation(s)
- Xue Jiang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Hor-Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Shanshan Teng
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
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19
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Schulte L, Scheiner B, Voigtländer T, Koch S, Schweitzer N, Marhenke S, Ivanyi P, Manns MP, Rodt T, Hinrichs JB, Weinmann A, Pinter M, Vogel A, Kirstein MM. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int 2019; 39:714-726. [PMID: 30663219 DOI: 10.1111/liv.14048] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/07/2019] [Accepted: 01/09/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. CONCLUSION Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.
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Affiliation(s)
- Lena Schulte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sandra Koch
- Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Nora Schweitzer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Philipp Ivanyi
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Rodt
- Hannover Medical School, Institute for Diagnostic and Interventional Radiology, Hannover, Germany
| | - Jan B Hinrichs
- Hannover Medical School, Institute for Diagnostic and Interventional Radiology, Hannover, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, Huttenlocher A. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol 2019; 70:710-721. [PMID: 30572006 PMCID: PMC6436385 DOI: 10.1016/j.jhep.2018.11.034] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 11/19/2018] [Accepted: 11/26/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) is an increasing clinical problem associated with progression to hepatocellular carcinoma (HCC). The effect of a high-fat diet on the early immune response in HCC is poorly understood, while the role of metformin in treating NAFLD and HCC remains controversial. Herein, we visualized the early immune responses in the liver and the effect of metformin on progression of HCC using optically transparent zebrafish. METHODS We used live imaging to visualize liver inflammation and disease progression in a NAFLD/NASH-HCC zebrafish model. We combined a high-fat diet with a transgenic zebrafish HCC model induced by hepatocyte-specific activated beta-catenin and assessed liver size, angiogenesis, micronuclei formation and inflammation in the liver. In addition, we probed the effects of metformin on immune cell composition and early HCC progression. RESULTS We found that a high-fat diet induced an increase in liver size, enhanced angiogenesis, micronuclei formation and neutrophil infiltration in the liver. Although macrophage number was not affected by diet, a high-fat diet induced changes in macrophage morphology and polarization with an increase in liver associated TNFα-positive macrophages. Treatment with metformin altered macrophage polarization, reduced liver size and reduced micronuclei formation in NAFLD/NASH-associated HCC larvae. Moreover, a high-fat diet reduced T cell density in the liver, which was reversed by treatment with metformin. CONCLUSIONS These findings suggest that diet alters macrophage polarization and exacerbates the liver inflammatory microenvironment and cancer progression in a zebrafish model of NAFLD/NASH-associated HCC. Metformin specifically affects the progression induced by diet and modulates the immune response by affecting macrophage polarization and T cell infiltration, suggesting possible effects of metformin on tumor surveillance. LAY SUMMARY This paper reports a new zebrafish model that can be used to study the effects of diet on liver cancer. We found that a high-fat diet promotes non-resolving inflammation in the liver and enhances cancer progression. In addition, we found that metformin, a drug used to treat diabetes, inhibits high-fat diet-induced cancer progression in this model, by reducing diet-induced non-resolving inflammation and potentially restoring tumor surveillance.
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Affiliation(s)
- Sofia de Oliveira
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States.
| | - Ruth A Houseright
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States
| | - Alyssa L Graves
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States
| | - Netta Golenberg
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States
| | - Benjamin G Korte
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States
| | - Veronika Miskolci
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States
| | - Anna Huttenlocher
- Department of Medical Microbiology and Immunology, University of Wisconsin Madison, Madison, United States; Department of Pediatrics, University of Wisconsin-Madison, Madison, United States.
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Wang YS, Du L, Liang X, Meng P, Bi L, Wang YL, Wang C, Tang B. Sirtuin 4 Depletion Promotes Hepatocellular Carcinoma Tumorigenesis Through Regulating Adenosine-Monophosphate-Activated Protein Kinase Alpha/Mammalian Target of Rapamycin Axis in Mice. Hepatology 2019; 69:1614-1631. [PMID: 30552782 DOI: 10.1002/hep.30421] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 11/23/2018] [Indexed: 12/15/2022]
Abstract
Sirtuin 4 (SIRT4) has been reported to play a vital role in the maintenance of glutamine catabolism and adenosine triphosphate (ATP) homeostasis, but its character in hepatocellular carcinomas (HCCs) remains obscure. In this study, we observed low expression of SIRT4 in both HCC cell lines and HCCs from patients. Decreased disease-free survival time is associated with low tumor levels of SIRT4 in patients. Deficiency of SIRT4 facilitated liver tumor development and lung metastasis in xenografts and knockout (KO) mice by promoting colony formation and migration of hepatoma cells and enhancing sphere formation of HCCs. Mechanistically, SIRT4 deletion augmented mammalian target of rapamycin (mTOR) signaling by inactivating adenosine-monophosphate (AMP)-activated protein kinase alpha (AMPKα) through regulation of glutamine catabolism and subsequent AM)/liver kinase B1 (LKB1) axis. Blockage of mTOR by rapamycin or inhibition of glutaminolysis abolished the discrepancy in tumorigenic capacity between SIRT4-depleted hepatoma cells and control cells. Suppression of LKB1 or promotion of AMP by metformin also abrogated the hyperproliferative phenotype caused by SIRT4 loss, which further confirmed that the LKB1/AMPKα/mTOR axis is required in SIRT4-deficiency-promoted HCC tumorigenesis. Conclusion: SIRT4 could exert its tumor suppressive function in HCC by inhibiting glutamine metabolism and thereby increasing the adenosine diphosphate (ADP)/AMP levels to phosphorylate AMPKα by LKB1, which blocks the mTOR signaling pathway.
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Affiliation(s)
- Yun-Shan Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China.,Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Xingsi Liang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Peng Meng
- Zhangjiang Center for Translational Medicine, Biotecan Medical Diagnostics Co., Ltd, Shanghai, China
| | - Lei Bi
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu-Li Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Bo Tang
- Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA.,School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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Safe S, Nair V, Karki K. Metformin-induced anticancer activities: recent insights. Biol Chem 2018; 399:321-335. [PMID: 29272251 DOI: 10.1515/hsz-2017-0271] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 12/11/2017] [Indexed: 12/12/2022]
Abstract
Metformin is a widely used antidiabetic drug, and there is evidence among diabetic patients that metformin is a chemopreventive agent against multiple cancers. There is also evidence in human studies that metformin is a cancer chemotherapeutic agent, and several clinical trials that use metformin alone or in combination with other drugs are ongoing. In vivo and in vitro cancer cell culture studies demonstrate that metformin induces both AMPK-dependent and AMPK-independent genes/pathways that result in inhibition of cancer cell growth and migration and induction of apoptosis. The effects of metformin in cancer cells resemble the patterns observed after treatment with drugs that downregulate specificity protein 1 (Sp1), Sp3 and Sp4 or by knockdown of Sp1, Sp3 and Sp4 by RNA interference. Studies in pancreatic cancer cells clearly demonstrate that metformin decreases expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes, demonstrating that one of the underlying mechanisms of action of metformin as an anticancer agent involves targeting of Sp transcription factors. These observations are consistent with metformin-mediated effects on genes/pathways in many other tumor types.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Vijayalekshmi Nair
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
| | - Keshav Karki
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA
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Cao X, Wu Y, Wang J, Liu K, Wang X. The Effect of Metformin on Mortality Among Diabetic Cancer Patients: A Systematic Review and Meta-analysis. JNCI Cancer Spectr 2017; 1:pkx007. [PMID: 31360833 PMCID: PMC6649807 DOI: 10.1093/jncics/pkx007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/16/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Most data suggest that cancer patients with diabetes have worse outcomes, which may be reversed with metformin. Metformin might modulate the clinical outcomes of diabetic cancer patients. We performed a systematic review and meta-analysis based on published studies over the past five years to summarize the effects of metformin on diabetic cancer patients. METHODS We systematically searched for studies that were published over the past five years. Then, we evaluated these studies for inclusion and extracted the relevant data. The summary risk estimates for the association between metformin treatment and all-cause mortality (ACM) and cancer-specific mortality (CSM) were analyzed using random or fixed-effects models. Stratified analyses by cancer site and country were also conducted. RESULTS Based on the 42 studies included in our analysis (37 015 diabetic cancer patients), we found a significant benefit associated with metformin treatment on survival corresponding to 27% and 26% reductions in ACM (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.68 to 0.79, P < .001) and CSM (HR = 0.74, 95% CI = 0.64 to 0.86, P < .001), respectively. The ACM rates for colorectal cancer, endometrial cancer, breast cancer, prostate cancer, and ovarian cancer showed significant benefits associated with metformin treatment in our stratified analyses by cancer site. Stratified analyses by cancer site also showed a significant reduction in CSM for breast cancer. This association between metformin treatment and reduced CSM for diabetic breast cancer patients was also observed in our country subgroup analyses. CONCLUSIONS We found an association between metformin exposure and reduced ACM and CSM in diabetic patients with cancer. Our findings suggest that metformin treatment could be an effective treatment option for diabetic cancer patients.
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Affiliation(s)
- Xun Cao
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Yaopan Wu
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Jing Wang
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Kuiyuan Liu
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Xin Wang
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
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Labenz C, Prenosil V, Koch S, Huber Y, Marquardt JU, Schattenberg JM, Galle PR, Weinmann A, Wörns MA. Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib. Dig Dis 2017; 36:78-88. [PMID: 28675895 DOI: 10.1159/000477578] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/15/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND/AIM Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. METHODS Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. RESULTS The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. CONCLUSIONS Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib.
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Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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25
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Ma SJ, Zheng YX, Zhou PC, Xiao YN, Tan HZ. Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis. Oncotarget 2016; 7:66202-66211. [PMID: 27494848 PMCID: PMC5323227 DOI: 10.18632/oncotarget.11033] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 07/19/2016] [Indexed: 12/19/2022] Open
Abstract
Metformin has garnered considerable interest as a chemo-preventive and chemo-therapeutic agent given the increased risk of liver cancer among diabetic patients. This work was performed to illustrate the association between metformin use and survival of diabetic liver cancer patients. We conducted a comprehensive literature search of PubMed, Web of Science, Embase, BIOSIS Previews, Cochrane Library from inception to 12 May 2016. Meta-analyses were performed using Stata (version 12.0), with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) as effect measures. Eleven cohort studies involving 3452 liver cancer patients fulfilled the inclusion criteria. Meta-analyses showed that metformin use was associated with better survival (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002) of liver cancer patients, and the beneficial effect persisted (HR = 0.64; 95% CI, 0.42-0.97; p = 0.035) when the population was restricted to diabetic liver cancer patients. After adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The results indicated that metformin use improved survival of diabetic liver cancer patients. However, the results should be interpreted with caution given the possibility of residual confounding. Further prospective studies are still needed to confirm the prognostic benefit of metformin use.
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Affiliation(s)
- Shu-Juan Ma
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yi-Xiang Zheng
- Department of Infectious Disease, Viral Hepatitis Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Peng-Cheng Zhou
- Department of Infectious Disease, Viral Hepatitis Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yan-Ni Xiao
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Hong-Zhuan Tan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
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Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016; 65:1096-108. [PMID: 26856933 PMCID: PMC4943559 DOI: 10.1016/j.metabol.2016.01.001] [Citation(s) in RCA: 378] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 01/04/2016] [Accepted: 01/05/2016] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM.
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Affiliation(s)
- Jonathan M Hazlehurst
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE
| | - Conor Woods
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE
| | - Thomas Marjot
- Department of Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK, OX3 9DU
| | - Jeremy F Cobbold
- Department of Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK, OX3 9DU
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE.
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Seo YS, Kim YJ, Kim MS, Suh KS, Kim SB, Han CJ, Kim YJ, Jang WI, Kang SH, Tchoe HJ, Park CM, Jo AJ, Kim HJ, Choi JA, Choi HJ, Polak MN, Ko MJ. Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection: A Nationwide Population-Based Study. Medicine (Baltimore) 2016; 95:e3527. [PMID: 27124061 PMCID: PMC4998724 DOI: 10.1097/md.0000000000003527] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30-0.49) and retreatment events (HR 0.41, 95% CI 0.33-0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events.
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Affiliation(s)
- Young-Seok Seo
- From the Department of Radiation Oncology (Y-SS, M-SK, WIJ), Korea Institute of Radiological and Medical Sciences; Division for Healthcare Technology Assessment Research (Y-JK, M-SK, SHK, HJT, CMP, AJJ, HJK, JAC, MJK), National Evidence-based Healthcare Collaborating Agency; Department of General Surgery (K-SS), Seoul National University Hospital; Department of General Surgery (SBK); Department of Internal Medicine (CJH, YJK), Korea Institute of Radiological and Medical Sciences; Department of Anatomy (HJC), Seoul National University College of Medicine, Seoul, Korea; and Department of Oncology (MNP), McGill University, Montreal, QC, Canada
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28
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Bhat A, Sebastiani G, Bhat M. Systematic review: Preventive and therapeutic applications of metformin in liver disease. World J Hepatol 2015; 7:1652-1659. [PMID: 26140084 PMCID: PMC4483546 DOI: 10.4254/wjh.v7.i12.1652] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/05/2015] [Accepted: 06/08/2015] [Indexed: 02/06/2023] Open
Abstract
Metformin, a biguanide derivative, is the most commonly prescribed medication in the treatment of type 2 diabetes mellitus. More recently, the use of metformin has shown potential as a preventive and therapeutic agent for a broad spectrum of conditions, including liver disease and hepatic malignancies. In this systematic review, we critically analyze the literature behind the potential use of metformin across the spectrum of liver disease and malignancies. The PubMed and Ovid MEDLINE databases were searched from 2000 to March 2015, using a combination of relevant text words and MeSH terms: metformin and mammalian target of rapamycin, hepatitis B virus (HBV), hepatitis B virus (HCV), non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) or cholangiocarcinoma. The search results were evaluated for pertinence to the issue of metformin in liver disease as well as for quality of study design. Metformin has a number of biochemical effects that would suggest a benefit in treating chronic liver diseases, particularly in the context of insulin resistance and inflammation. However, the literature thus far does not support any independent therapeutic role in NAFLD or HCV. Nonetheless, there is Level III evidence for a chemopreventive role in patients with diabetes and chronic liver disease, with decreased incidence of HCC and cholangiocarcinoma. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. In conclusion, there is insufficient evidence to recommend use of metformin in the adjunctive treatment of chronic liver diseases, including NAFLD and HCV. However, there is good evidence for a chemopreventive role against HCC among patients with diabetes and chronic liver disease, and metformin should be continued in patients even with cirrhosis to provide this benefit.
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29
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Thompson AI, Conroy KP, Henderson NC. Hepatic stellate cells: central modulators of hepatic carcinogenesis. BMC Gastroenterol 2015; 15:63. [PMID: 26013123 PMCID: PMC4445994 DOI: 10.1186/s12876-015-0291-5] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 05/15/2015] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90 % of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC.
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Affiliation(s)
- Alexandra I Thompson
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
| | - Kylie P Conroy
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
| | - Neil C Henderson
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
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