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Papaefthymiou A, Landi R, Arvanitakis M, Tringali A, Gkolfakis P. Endoscopic retrograde cholangiopancreatography: A comprehensive review as a single diagnostic tool. Best Pract Res Clin Gastroenterol 2025; 74:101976. [PMID: 40210330 DOI: 10.1016/j.bpg.2025.101976] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/17/2024] [Accepted: 12/18/2024] [Indexed: 04/12/2025]
Abstract
Endoscopic retrograde cholangiopancreatography (ERCP) was initially introduced in clinical practice as diagnostic tool. However, the presence of adverse events and the development of non-invasive techniques, such as magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS), limited its role as a stand-alone diagnostic choice, modifying its role to the leader of therapeutic pancreatobiliary endoscopy. Despite technological advances, there are still conditions where non-invasive diagnostic modalities are inconclusive, such as indeterminate biliary and pancreatic duct strictures, primary sclerosing cholangitis functional stenoses, intraductal papillary mucinous neoplasms (IPMNs) and paediatric indications, such as congenital anatomical abnormalities. This narrative review aimed to identify and analyse indications of diagnostic ERCP, without the need for therapeutic manipulations.
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Affiliation(s)
| | - Rosario Landi
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy; Università Cattolica del Sacro Cuore, Centre for Endoscopic Research Therapeutics and Training (CERTT), Rome, Italy
| | - Marianna Arvanitakis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, ULB, Brussels, Belgium
| | - Andrea Tringali
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy; Università Cattolica del Sacro Cuore, Centre for Endoscopic Research Therapeutics and Training (CERTT), Rome, Italy
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, ULB, Brussels, Belgium; Department of Gastroenterology, General Hospital of Nea Ionia "Konstantopoulio-Patision", Athens, Greece.
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2
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Rattanasinchai C, Navasumrit P, Chornkrathok C, Ruchirawat M. Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167521. [PMID: 39369614 DOI: 10.1016/j.bbadis.2024.167521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive. METHODS The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated. RESULTS Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations. CONCLUSIONS IGF-1R plays a critical role in maintaining iCCA-stem like cell populations. GENERAL SIGNIFICANCE Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.
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Affiliation(s)
- Chotirat Rattanasinchai
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Panida Navasumrit
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Chidchanok Chornkrathok
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Mathuros Ruchirawat
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand.
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3
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Vitale F, Zileri Dal Verme L, Paratore M, Negri M, Nista EC, Ainora ME, Esposto G, Mignini I, Borriello R, Galasso L, Alfieri S, Gasbarrini A, Zocco MA, Nicoletti A. The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines 2024; 12:2840. [PMID: 39767746 PMCID: PMC11673965 DOI: 10.3390/biomedicines12122840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/30/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Pancreatic cancer is one of the most aggressive cancers with a very poor 5-year survival rate and reduced therapeutic options when diagnosed in an advanced stage. The dismal prognosis of pancreatic cancer has guided significant efforts to discover novel biomarkers in order to anticipate diagnosis, increasing the population of patients who can benefit from curative surgical treatment. CA 19-9 is the reference biomarker that supports the diagnosis and guides the response to treatments. However, it has significant limitations, a low specificity, and is inefficient as a screening tool. Several potential biomarkers have been discovered in the serum, urine, feces, and pancreatic juice of patients. However, most of this evidence needs further validation in larger cohorts. The advent of advanced omics sciences and liquid biopsy techniques has further enhanced this field of research. The aim of this review is to analyze the historical evolution of the research on novel biomarkers for the early diagnosis of pancreatic cancer, focusing on the current evidence for the most promising biomarkers from different body fluids and the novel trends in research, such as omics sciences and liquid biopsy, in order to favor the application of modern personalized medicine.
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Affiliation(s)
- Federica Vitale
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Lorenzo Zileri Dal Verme
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Mattia Paratore
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Marcantonio Negri
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Enrico Celestino Nista
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Elena Ainora
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Giorgio Esposto
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Irene Mignini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Raffaele Borriello
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Linda Galasso
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Sergio Alfieri
- Centro Pancreas, Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy;
| | - Antonio Gasbarrini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Assunta Zocco
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Alberto Nicoletti
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
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Di Stasi V, Contaldo A, Birtolo LI, Shahini E. Interplay of Cardiometabolic Syndrome and Biliary Tract Cancer: A Comprehensive Analysis with Gender-Specific Insights. Cancers (Basel) 2024; 16:3432. [PMID: 39410050 PMCID: PMC11476000 DOI: 10.3390/cancers16193432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/05/2024] [Accepted: 10/09/2024] [Indexed: 10/20/2024] Open
Abstract
BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.
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Affiliation(s)
- Vincenza Di Stasi
- Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy;
| | - Antonella Contaldo
- Gastroenterology Unit, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy;
| | - Lucia Ilaria Birtolo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Umberto I Hospital, Sapienza University of Rome, 00185 Rome, Italy;
| | - Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy;
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Affarah L, Berry P, Kotha S. Still elusive: Developments in the accurate diagnosis of indeterminate biliary strictures. World J Gastrointest Endosc 2024; 16:297-304. [PMID: 38946851 PMCID: PMC11212512 DOI: 10.4253/wjge.v16.i6.297] [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: 01/29/2024] [Revised: 04/09/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024] Open
Abstract
Indeterminate biliary strictures pose a significant diagnostic dilemma for gastroenterologists. Despite advances in endoscopic techniques and instruments, it is difficult to differentiate between benign and malignant pathology. A positive histological diagnosis is always preferred prior to high risk hepatobiliary surgery, or to inform other types of therapy. Endoscopic retrograde cholangiopancreatography with brushings has low sensitivity and despite significant improvements in instruments there is still an unacceptably high false negative rate. Other methods such as endoscopic ultrasound and cholangioscopy have improved diagnostic quality. In this review we explore the techniques available to aid accurate diagnosis of indeterminate biliary strictures and obtain accurate histology to facilitate clinical management.
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Affiliation(s)
- Lynn Affarah
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Philip Berry
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Sreelakshmi Kotha
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
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Qin L, Kuai J, Yang F, Yang L, Sun P, Zhang L, Li G. Selected by bioinformatics and molecular docking analysis, Dhea and 2-14,15-Eg are effective against cholangiocarcinoma. PLoS One 2022; 17:e0260180. [PMID: 35113866 PMCID: PMC8812988 DOI: 10.1371/journal.pone.0260180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/03/2021] [Indexed: 12/04/2022] Open
Abstract
OBJECT To identify novel targets for the diagnosis, treatment and prognosis of cholangiocarcinoma, we screen ideal lead compounds and preclinical drug candidates with MYC inhibitory effect from the ZINC database, and verify the therapeutic effect of Dhea and 2-14,15-Eg on cholangiocarcinoma. METHODS The gene expression profiles of GSE132305, GSE89749, and GSE45001 were obtained respectively from the Gene Expression Omnibus database. The DEGs were identified by comparing the gene expression profiles of cholangiocarcinoma and normal tissues. GO, KEGG analysis and PPI network analyses were performed. LibDock, ADME and toxicity prediction, molecular docking and molecular dynamics simulations were used to identify potential inhibitors of MYC. Moreover, in vitro, MTT assay, colony-forming assay, the scratch assay and Western blotting were performed to verify the therapeutic effect of Dhea and 2-14,15-Eg. RESULTS PPI network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study. A battery of computer-aided virtual techniques showed that Dhea and 2-14,15-Eg have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6, as well as could exist stably in natural circumstances. In vitro assays showed that Dhea and 2-14,15-Eg inhibited cholangiocarcinoma cellular viability, proliferation, and migration inhibiting expression of MYC. CONCLUSION This study suggested that Dhea and 2-14,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application.
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Affiliation(s)
- Lei Qin
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Jun Kuai
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Fang Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Lu Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Peisheng Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Lanfang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
| | - Guangpeng Li
- Department of Emergency, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang, China
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Osataphan S, Mahankasuwan T, Saengboonmee C. Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:1047-1059. [PMID: 34053180 DOI: 10.1002/jhbp.1001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/02/2021] [Accepted: 05/19/2021] [Indexed: 11/10/2022]
Abstract
Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelium, and its incidence is increasing globally. Numerous factors are reported associated with an increased risk of CCA and vary among populations across different areas. Obesity is a major, worldwide public health problem that leads to several complications and is associated with increased cancer risk. Although several epidemiological studies have shown that obesity is likely associated with the increased risk of CCA, this association might be limited to Western countries. Multiple hormones, cytokines, and metabolite perturbations in obese states have been shown to enhance tumorigenicity and metastasis potentials. Understanding the biological linkage of obesity to CCA might lead to novel prevention and therapeutic approaches to CCA treatment. This review summarizes the current evidence and highlights the knowledge gaps regarding the relationship between obesity and CCA from epidemiological and molecular perspectives.
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Affiliation(s)
| | | | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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Ghidini M, Ramai D, Facciorusso A, Singh J, Tai W, Rijavec E, Galassi B, Grossi F, Indini A. Metabolic disorders and the risk of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:999-1007. [PMID: 34423721 DOI: 10.1080/17474124.2021.1946393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy which arises from the biliary epithelium. Carcinogenesis of CCA is mainly linked to aberrant glucose metabolism and creation of an immunosuppressive environment around normal biliary epithelium. The incidence of CCA is higher in the East due to Opisthorchis viverrini, an endemic liver fluke. CCA has also be attributed to genetic, metabolic, and lifestyle risk factors.Areas covered: Differences in epidemiological risk factors are associated with varying phenotypes of CCA. Metabolic risk factors include diabetes, obesity, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome. Inherited metabolic risk factors include Wilson's disease and hemochromatosis. Metabolic disease is associated with a higher risk of CCA, with higher risk for the intrahepatic form. In this review, the authors provide an overview of available evidence regarding metabolic conditions associated with the development of CCA.Expert opinion: Metabolic disease is associated with a higher risk of intrahepatic CCA compared to its extrahepatic or hilar counterpart. As rates of obesity and metabolic syndrome increase, particularly in the West, it is conceivable that the incidence of CCA will also rise in the next years.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, USA
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Foggia, Italy
| | - Jameel Singh
- Department of Internal Medicine, Mather Hospital, Northwell Health, Port Jefferson, New York, USA
| | - Waqqas Tai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, USA
| | - Erika Rijavec
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Barbara Galassi
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Grossi
- Department of Medicine and Surgery, Medical Oncology Unit, ASST Sette Laghi, Varese, Italy
| | - Alice Indini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol 2021; 27:4045-4087. [PMID: 34326612 PMCID: PMC8311531 DOI: 10.3748/wjg.v27.i26.4045] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).
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Affiliation(s)
- Robert S O'Neill
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
| | - Alina Stoita
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
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Saengboonmee C, Seubwai W, Lert-Itthiporn W, Sanlung T, Wongkham S. Association of Diabetes Mellitus and Cholangiocarcinoma: Update of Evidence and the Effects of Antidiabetic Medication. Can J Diabetes 2021; 45:282-290. [PMID: 33218924 DOI: 10.1016/j.jcjd.2020.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/03/2020] [Accepted: 09/11/2020] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus (DM) is a risk factor for cancer in many organs and associated with an increased risk of cholangiocarcinoma (CCA). The molecular linkage between these diseases has been demonstrated in preclinical studies, which have highlighted the role of hyperinsulinemia and hyperglycemia in the carcinogenesis and progression of CCA. Recent studies on the emerging role of antidiabetic medication in the development and progression of CCA showed a subclass of antidiabetic drug with a therapeutic effect on CCA. Although associations between CCA, insulin analogues and sulfonylureas are unclear, incretin-based therapy is likely associated with an increased risk for CCA, and may lead to CCA progression, as demonstrated by in vitro and in vivo experiments. In contrast, biguanides, especially metformin, exert an opposite effect, associated with a reduced risk of CCA and inhibited in vitro and in vivo CCA progression. The association between incretin-based therapy and the risk of CCA needs further clarification, as metformin is being studied in an ongoing clinical trial. Understanding the association between DM and CCA is critical for preventing the development of CCA in patients with DM, and for establishing the appropriateness of antidiabetic medication to treat CCA. Determining how metformin affects CCA can lead to repurposing this safe and well-known drug for improving CCA treatment, regardless of the diabetes status of patients.
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Affiliation(s)
- Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States.
| | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thanachai Sanlung
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Adrait A, Dumonceau JM, Delhaye M, Annessi-Ramseyer I, Frossard JL, Couté Y, Farina A. Liquid Biopsy of Bile based on Targeted Mass Spectrometry for the Diagnosis of Malignant Biliary Strictures. Clin Transl Sci 2020; 14:148-152. [PMID: 33048472 PMCID: PMC7877827 DOI: 10.1111/cts.12890] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022] Open
Abstract
Bile holds biomarkers of malignant biliary strictures (MBS) but is unsuited for automated analyzers used in routine diagnostic laboratories. Selected reaction monitoring (SRM) is a flexible high‐throughput analytical approach based on targeted mass spectrometry (MS) already implemented in clinical settings. We tested the hypothesis that SRM could be used to quantify cancer biomarkers in human bile. An SRM‐based assay was developed to simultaneously quantify up to 37 peptides from 13 bile proteins in a developmental cohort of 15 patients (MBS, n = 8; benign biliary stricture or obstruction (BBS), n = 7). The most reliable biomarkers were then absolutely quantified by SRM in a verification cohort of 67 patients (MBS, n = 37; BBS, n = 30). The diagnostic performances of single and combined biomarkers were assessed. In the developmental cohort, SRM‐based analysis revealed six protein biomarkers with significantly higher peptide ratios (endogenous vs. standard) in bile from MBS vs. BBS. In the verification cohort, five of these biomarkers proved good diagnostic ability (individual receiver operating characteristic‐area under the receiver operating characteristic curve (ROC‐AUC) up to 0.889, accuracies from 67.8% to 83.1%). Combining bile biomarkers and serum CA19‐9 in 2 panels allowed differentiating MBS from BBS with up to 0.929 ROC‐AUC and 89.8% accuracy. In this study, a newly developed SRM‐based assay proved able to simultaneously quantify multiple biomarkers in bile samples. The combination of bile biomarkers with serum CA19‐9 was highly accurate for the diagnosis of MBS. Liquid biopsy of bile based on targeted MS is eligible to support MBS diagnosis in clinical practice.
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Affiliation(s)
- Annie Adrait
- University Grenoble Alpes, CEA, Inserm, IRIG, BGE, Grenoble, France
| | | | - Myriam Delhaye
- Department of Gastroenterology, Hepatopancreatology and GI Oncology, Erasme University Hospital, Brussels, Belgium
| | | | - Jean-Louis Frossard
- Department of Medicine, Geneva University, Geneva, Switzerland.,Division of Gastroenterology, Geneva University Hospitals, Geneva, Switzerland
| | - Yohann Couté
- University Grenoble Alpes, CEA, Inserm, IRIG, BGE, Grenoble, France
| | - Annarita Farina
- Department of Medicine, Geneva University, Geneva, Switzerland.,Division of Gastroenterology, Geneva University Hospitals, Geneva, Switzerland
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Sato K, Francis H, Zhou T, Meng F, Kennedy L, Ekser B, Baiocchi L, Onori P, Mancinelli R, Gaudio E, Franchitto A, Glaser S, Alpini G. Neuroendocrine Changes in Cholangiocarcinoma Growth. Cells 2020; 9:436. [PMID: 32069926 PMCID: PMC7072848 DOI: 10.3390/cells9020436] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/09/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA-intrahepatic, hilar (perihilar), or distal (extrahepatic)-according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.
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Affiliation(s)
- Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | | | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
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Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell. BMC Gastroenterol 2018; 18:169. [PMID: 30400838 PMCID: PMC6220519 DOI: 10.1186/s12876-018-0870-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 09/10/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a form of cancer that easily aggress to contiguous structures. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) are increased in majority species of cancers and suppress tumor progression by blocking VEGF/VEGFR2. Apatinib is a highly selective VEGFR2 antagonist which has inhibitive effect on antiapoptotic and cell growth in CCA. While, the effect of apatinib cell migration and invasion in CCA is still unknown. METHODS CCA cell lines QBC939 and TFK-1 were transfected with siKDR to establish the KDR function loss cell model, and recombined human VEGF (rhVEGF) protein was added into the culture medium to enhance the VEGF expression. RT-qPCR and western bloting were used to detect the mRNA and protein expression levels of VEGFR2 to investigate whether it was effectively repressed or activated with rhVEGF or apatinib treatment. Then, MTT, wound healing assay, and transwell matrix assay were applied to measure the effect of apatinib and rhVEGF on cell viability, migration and invasion, respectively. RESULTS The mRNA and protein expressions of VEGFR2 were significantly reduced with KDR RNAi in both QBC939 and TFK-1 cells, and rhVEGF treatment increased these expression levels (p < 0.05). Apatinib dramatically suppressed VEGF-mediated cell migration and invasion at the concentration of 100 nM treatment and significantly decreased the expression of metastasis-associated protein such as Slug, snail and MMP9. Moreover, all of these inhibiting effects of apatinib depended on the VEGFR2 existence. In addition, VEGFR2/RAF/MEK/ERK and PI3K/AKT signal pathways were enhanced by the introduction of rhVEGF, but were dramatically suppressed after the apatinib treatment. CONCLUSION Apatinib inhibit VEGF-mediated cell migration and invasion in CCA cell lines via inhibiting the VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways. It will be a potentially effective targeted drug for CCA.
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Keane MG, Shah A, Pereira SP, Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy. F1000Res 2017; 6:1643. [PMID: 28944047 PMCID: PMC5585877 DOI: 10.12688/f1000research.11371.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2017] [Indexed: 12/12/2022] Open
Abstract
The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1–2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review.
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Affiliation(s)
| | - Amar Shah
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Stephen P Pereira
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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