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1
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Dong H, Chen R, Wang J, Chai N, Linghu E. Can NPC1L1 inhibitors reduce the risk of biliary tract cancer? Evidence from a mendelian randomization study. Dig Liver Dis 2024; 56:1599-1604. [PMID: 38342741 DOI: 10.1016/j.dld.2024.01.211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/28/2024] [Accepted: 01/29/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND & AIMS Oxysterols have been implicated in biliary tract cancer (BTC), and Niemann-Pick C1-like 1 (NPC1L1) has been associated with oxysterol uptake in biliary and intestinal cells. Thus, our study aims to investigate the potential causal link between genetically proxied NPC1L1 inhibitors and the risk of BTC. METHODS In this study, we employed two genetic instruments as proxies for NPC1L1 inhibitors, which included LDL cholesterol-associated genetic variants located within or in close proximity to the NPC1L1 gene, as well as expression quantitative trait loci (eQTLs) of the NPC1L1 gene. Effect estimates were calculated using the Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) methods. RESULTS In MR analysis using the IVW method, both proxy instruments from the UK Biobank and the GLGC demonstrated a positive association between NPC1L1-mediated LDL cholesterol and BTC risk, with odds ratios (OR) of 10.30 (95% CI = 1.51-70.09; P = 0.017) and 5.61 (95% CI = 1.43-21.91; P = 0.013), respectively. Moreover, SMR analysis revealed a significant association between elevated NPC1L1 expression and increased BTC risk (OR = 1.19, 95% CI = 1.04-1.37; P = 0.014). CONCLUSIONS This MR study suggests a causal link between NPC1L1 inhibition and reduced BTC risk. NPC1L1 inhibitors, like ezetimibe, show potential for chemoprevention in precancerous BTC patients, requiring further clinical investigation.
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Affiliation(s)
- Hao Dong
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Rong Chen
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China
| | - Jiafeng Wang
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Ningli Chai
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, PR China.
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, PR China.
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2
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Dias IHK, Shokr H. Oxysterols as Biomarkers of Aging and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:307-336. [PMID: 38036887 DOI: 10.1007/978-3-031-43883-7_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Oxysterols derive from either enzymatic or non-enzymatic oxidation of cholesterol. Even though they are produced as intermediates of bile acid synthesis pathway, they are recognised as bioactive compounds in cellular processes. Therefore, their absence or accumulation have been shown to be associated with disease phenotypes. This chapter discusses the contribution of oxysterol to ageing, age-related diseases such as neurodegeneration and various disorders such as cancer, cardiovascular disease, diabetes, metabolic and ocular disorders. It is clear that oxysterols play a significant role in development and progression of these diseases. As a result, oxysterols are being investigated as suitable markers for disease diagnosis purposes and some drug targets are in development targeting oxysterol pathways. However, further research will be needed to confirm the suitability of these potentials.
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Affiliation(s)
- Irundika H K Dias
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, UK.
| | - Hala Shokr
- Manchester Pharmacy School, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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3
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Caligiuri A, Becatti M, Porro N, Borghi S, Marra F, Pastore M, Taddei N, Fiorillo C, Gentilini A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants (Basel) 2023; 13:28. [PMID: 38247453 PMCID: PMC10812651 DOI: 10.3390/antiox13010028] [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: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
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Affiliation(s)
- Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Nunzia Porro
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Serena Borghi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
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4
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Lu J, Chen S, Bai X, Liao M, Qiu Y, Zheng LL, Yu H. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications. Biochem Pharmacol 2023; 218:115907. [PMID: 37931664 DOI: 10.1016/j.bcp.2023.115907] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023]
Abstract
Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.
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Affiliation(s)
- Jia Lu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Siwei Chen
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xuejiao Bai
- Department of Anesthesiology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minru Liao
- Department of Anesthesiology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuling Qiu
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
| | - Ling-Li Zheng
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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5
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Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14:230-246. [PMID: 37583950 PMCID: PMC10424089 DOI: 10.5306/wjco.v14.i7.230] [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: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/21/2023] [Indexed: 07/19/2023] Open
Abstract
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Perth 6009, Crawley NA, Australia
- Department of Medical Oncology, Sir Charles Gardner Hospital, Nedlands 6009, Australia
| | - Angela Felicia Sunjaya
- Institute of Cardiovascular Science, University College London, London WC1E 6DD, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland 6056, WA, Australia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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6
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Cai X, Tacke F, Guillot A, Liu H. Cholangiokines: undervalued modulators in the hepatic microenvironment. Front Immunol 2023; 14:1192840. [PMID: 37261338 PMCID: PMC10229055 DOI: 10.3389/fimmu.2023.1192840] [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: 03/24/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023] Open
Abstract
The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.
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Affiliation(s)
- Xiurong Cai
- Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Center of Gastrointestinal Diseases, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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7
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Cadamuro M, Al-Taee A, Gonda TA. Advanced endoscopy meets molecular diagnosis of cholangiocarcinoma. J Hepatol 2023; 78:1063-1072. [PMID: 36740048 DOI: 10.1016/j.jhep.2023.01.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/22/2022] [Accepted: 01/18/2023] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools.
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Affiliation(s)
| | - Ahmad Al-Taee
- Carle Illinois College of Medicine, University of Illinois Urbaba-Champaign, Champaign County, IL, USA
| | - Tamas A Gonda
- Division of Gastroenterology and Hepatology, New York University, New York, NY, USA.
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8
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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9
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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10
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Interplay between Dysbiosis of Gut Microbiome, Lipid Metabolism, and Tumorigenesis: Can Gut Dysbiosis Stand as a Prognostic Marker in Cancer? DISEASE MARKERS 2022; 2022:2941248. [PMID: 35178126 PMCID: PMC8847007 DOI: 10.1155/2022/2941248] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/11/2022] [Indexed: 02/07/2023]
Abstract
The gut bacterial community is involved in the metabolism of bile acids and short-chain fatty acids (SCFAs). Bile acids are involved in the absorption of fat and the regulation of lipid homeostasis through emulsification and are transformed into unconjugated bile acids by the gut microbiota. The gut microbiota is actively involved in the production of bile acid metabolites, such as deoxycholic acid, lithocholic acid, choline, and SCFAs such as acetate, butyrate, and propionate. Metabolites derived from the gut microbiota or modified gut microbiota metabolites contribute significantly to host pathophysiology. Gut bacterial metabolites, such as deoxycholic acid, contribute to the development of hepatocellular carcinoma and colon cancer by factors such as inflammation and oxidative DNA damage. Butyrate, which is derived from gut bacteria such as Megasphaera, Roseburia, Faecalibacterium, and Clostridium, is associated with the activation of Treg cell differentiation in the intestine through histone acetylation. Butyrate averts the action of class I histone deacetylases (HDAC), such as HDAC1 and HDAC3, which are responsible for the transcription of genes such as p21/Cip1, and cyclin D3 through hyperacetylation of histones, which orchestrates G1 cell cycle arrest. It is essential to identify the interaction between the gut microbiota and bile acid and SCFA metabolism to understand their role in gastrointestinal carcinogenesis including colon, gastric, and liver cancer. Metagenomic approaches with bioinformatic analyses are used to identify the bacterial species in the metabolism of bile acids and SCFAs. This review provides an overview of the current knowledge of gut microbiota-derived bile acid metabolism in tumor development and whether it can stand as a marker for carcinogenesis. Additionally, this review assesses the evidence of gut microbiota-derived short-chain fatty acids including butyric acid in antitumor activity. Future research is required to identify the beneficial commensal gut bacteria and their metabolites which will be considered to be therapeutic targets in inflammation-mediated gastrointestinal cancers.
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11
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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12
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Mechanism of cholangiocellular damage and repair during cholestasis. Ann Hepatol 2021; 26:100530. [PMID: 34509686 DOI: 10.1016/j.aohep.2021.100530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/30/2021] [Accepted: 04/30/2021] [Indexed: 02/04/2023]
Abstract
The mechanism of damage of the biliary epithelium remains partially unexplored. However, recently many works have offered new evidence regarding the cholangiocytes' damage process, which is the main target in a broad spectrum of pathologies ranging from acute cholestasis, cholangiopathies to cholangiocarcinoma. This is encouraging since some works addressed this epithelium's relevance in health and disease until a few years ago. The biliary tree in the liver, comprised of cholangiocytes, is a pipeline for bile flow and regulates key hepatic processes such as proliferation, regeneration, immune response, and signaling. This review aimed to compile the most recent advances on the mechanisms of cholangiocellular damage during cholestasis, which, although it is present in many cholangiopathies, is not necessarily a common or conserved process in all of them, having a relevant role cAMP and PKA during obstructive cholestasis, as well as Ca2+-dependent PKC in functional cholestasis. Cholangiocellular damage could vary according to the type of cholestasis, the aggressor, or the bile ducts' location where it develops and what kind of damage can favor cholangiocellular carcinoma development.
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13
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Garcia-Ruiz C, Conde de la Rosa L, Ribas V, Fernandez-Checa JC. MITOCHONDRIAL CHOLESTEROL AND CANCER. Semin Cancer Biol 2021; 73:76-85. [PMID: 32805396 PMCID: PMC7882000 DOI: 10.1016/j.semcancer.2020.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/11/2022]
Abstract
Cholesterol is a crucial component of membrane bilayers that determines their physical and functional properties. Cells largely satisfy their need for cholesterol through the novo synthesis from acetyl-CoA and this demand is particularly critical for cancer cells to sustain dysregulated cell proliferation. However, the association between serum or tissue cholesterol levels and cancer development is not well established as epidemiologic data do not consistently support this link. While most preclinical studies focused on the role of total celular cholesterol, the specific contribution of the mitochondrial cholesterol pool to alterations in cancer cell biology has been less explored. Although low compared to other bilayers, the mitochondrial cholesterol content plays an important physiological function in the synthesis of steroid hormones in steroidogenic tissues or bile acids in the liver and controls mitochondrial function. In addition, mitochondrial cholesterol metabolism generates oxysterols, which in turn, regulate multiple pathways, including cholesterol and lipid metabolism as well as cell proliferation. In the present review, we summarize the regulation of mitochondrial cholesterol, including its role in mitochondrial routine performance, cell death and chemotherapy resistance, highlighting its potential contribution to cancer. Of particular relevance is hepatocellular carcinoma, whose incidence in Western countries had tripled in the past decades due to the obesity and type II diabetes epidemic. A better understanding of the role of mitochondrial cholesterol in cancer development may open up novel opportunities for cancer therapy.
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Affiliation(s)
- Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Vicent Ribas
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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14
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Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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15
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Cholesterol metabolism: New functions and therapeutic approaches in cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188394. [PMID: 32698040 DOI: 10.1016/j.bbcan.2020.188394] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/08/2020] [Accepted: 07/12/2020] [Indexed: 02/05/2023]
Abstract
Cholesterol and its metabolites (precursors and derivatives) play an important role in cancer. In recent years, numerous studies have reported the functions of cholesterol metabolism in the regulation of tumor biological processes, especially oncogenic signaling pathways, ferroptosis, and tumor microenvironment. Preclinical studies have over the years indicated the inhibitory effects of blocking cholesterol synthesis and uptake on tumor formation and growth. Besides, some new cholesterol metabolic molecules such as SOAT1, SQLE, and NPC1 have recently emerged as promising drug targets for cancer treatment. Here, we systematically review the roles of cholesterol and its metabolites, and the latest advances in cancer therapy targeting cholesterol metabolism.
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16
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Vale N, Gouveia MJ, Gärtner F, Brindley PJ. Oxysterols of helminth parasites and pathogenesis of foodborne hepatic trematodiasis caused by Opisthorchis and Fasciola species. Parasitol Res 2020; 119:1443-1453. [PMID: 32206886 DOI: 10.1007/s00436-020-06640-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/25/2020] [Indexed: 02/06/2023]
Abstract
The foodborne trematodiases refer to a cluster of zoonotic neglected tropical diseases caused by trematodes, with transmission involving ingestion of contaminated plants, fishes, and crustaceans. Over 40 million people are infected with foodborne trematodes and 750 million are at risk of infection. From a public health point of view, important species include Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Fasciola hepatica, and Fasciola gigantica. Infection with C. sinensis and O. viverrini is classified as a group 1 biological carcinogen and a major risk factor for cholangiocarcinoma. The carcinogenic potential of the infection with O. felineus is less clear but recent biochemical and histopathological findings revealed that opisthorchiasis felinea also fits this pattern. By contrast, evidence of carcinogenic potential of infection with F. hepatica or F. gigantica, close phylogenetics relatives of Opisthorchis, is less certain. Oxysterols have been essentially described in animal model of opisthorchiasis and associated cholangiocarcinoma. Several oxysterol-like metabolites have been detected not only on developmental stages of O. viverrini and O. felineus but also on biofluids from experimentally infected hamsters as products of the activities of the liver flukes. These sterol derivatives are metabolized to active quinones that can modify host DNA. We have postulated that helminth parasite-associated sterols might induce tumor-like phenotypes in biliary epithelia, the cells of origin of liver fluke infection-associated cholangiocarcinoma, through the formation of DNA adducts, dysregulation of apoptosis, and other homeostatic pathways. Here we review, interpret, and discuss findings of oxysterol-like metabolites detected in liver flukes and their role in carcinogenesis, aiming to enhance understanding the pathogenesis of foodborne trematodiasis caused by Opisthorchis and Fasciola species. In future, further investigations will be necessary in order to comprehend relationship between liver flukes' oxysterols and their role in infection-associated diseases in humans.
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Affiliation(s)
- Nuno Vale
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 228, 4050-313, Porto, Portugal. .,Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal. .,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal. .,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.
| | - Maria João Gouveia
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal.,Center for the Study of Animal Science, CECA - ICETA, University of Porto, Praça Gomes Teixeira Apt 55142, 4051-401, Porto, Portugal
| | - Fátima Gärtner
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
| | - Paul J Brindley
- Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20052, USA
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17
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Riscal R, Skuli N, Simon MC. Even Cancer Cells Watch Their Cholesterol! Mol Cell 2019; 76:220-231. [PMID: 31586545 DOI: 10.1016/j.molcel.2019.09.008] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/30/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
Deregulated cell proliferation is an established feature of cancer, and altered tumor metabolism has witnessed renewed interest over the past decade, including the study of how cancer cells rewire metabolic pathways to renew energy sources and "building blocks" that sustain cell division. Microenvironmental oxygen, glucose, and glutamine are regarded as principal nutrients fueling tumor growth. However, hostile tumor microenvironments render O2/nutrient supplies chronically insufficient for increased proliferation rates, forcing cancer cells to develop strategies for opportunistic modes of nutrient acquisition. Recent work shows that cancer cells overcome this nutrient scarcity by scavenging other substrates, such as proteins and lipids, or utilizing adaptive metabolic pathways. As such, reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid-mediated signaling during cancer progression. In this review, we highlight more recently appreciated roles for lipids, particularly cholesterol and its derivatives, in cancer cell metabolism within intrinsically harsh tumor microenvironments.
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Affiliation(s)
- Romain Riscal
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicolas Skuli
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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18
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Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
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Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
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19
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Bragazzi MC, Ridola L, Safarikia S, Matteo SD, Costantini D, Nevi L, Cardinale V. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol 2017; 31:42-55. [PMID: 29333066 PMCID: PMC5759612 DOI: 10.20524/aog.2017.0209] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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20
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Chung BK, Karlsen TH, Folseraas T. Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1390-1400. [PMID: 28844951 DOI: 10.1016/j.bbadis.2017.08.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 08/16/2017] [Accepted: 08/21/2017] [Indexed: 12/15/2022]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC-associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells - a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Brian K Chung
- Centre for Liver Research and NIHR Birmingham Inflammation Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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21
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Kloudova A, Guengerich FP, Soucek P. The Role of Oxysterols in Human Cancer. Trends Endocrinol Metab 2017; 28:485-496. [PMID: 28410994 PMCID: PMC5474130 DOI: 10.1016/j.tem.2017.03.002] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 03/20/2017] [Indexed: 12/12/2022]
Abstract
Oxysterols are oxygenated derivatives of cholesterol formed in the human body or ingested in the diet. By modulating the activity of many proteins [e.g., liver X receptors (LXRs), oxysterol-binding proteins (OSBPs), some ATP-binding cassette (ABC) transporters], oxysterols can affect many cellular functions and influence various physiological processes (e.g., cholesterol metabolism, membrane fluidity regulation, intracellular signaling pathways). Therefore, the role of oxysterols is also important in pathological conditions (e.g., atherosclerosis, diabetes mellitus type 2, neurodegenerative disorders). Finally, current evidence suggests that oxysterols play a role in malignancies such as breast, prostate, colon, and bile duct cancer. This review summarizes the physiological importance of oxysterols in the human body with a special emphasis on their roles in various tumors.
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Affiliation(s)
- Alzbeta Kloudova
- Department of Toxicogenomics, National Institute of Public Health, Prague 100 42, Czech Republic; Third Faculty of Medicine, Charles University, Prague 100 00, Czech Republic
| | - F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Pavel Soucek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen 323 00, Czech Republic.
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22
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Proungvitaya S, Klinthong W, Proungvitaya T, Limpaiboon T, Jearanaikoon P, Roytrakul S, Wongkham C, Nimboriboonporn A, Wongkham S. High expression of CCDC25 in cholangiocarcinoma tissue samples. Oncol Lett 2017; 14:2566-2572. [PMID: 28789463 DOI: 10.3892/ol.2017.6446] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 03/17/2017] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant transformation of biliary epithelial cells. It is a slow growing tumor, but is also highly metastatic with a poor prognosis. Bile acids are known to transactivate the epidermal growth factor receptor (EGFR) in cholangiocytes and induce cyclooxygenase-2 expression. The protein expression profiles of bile acid-treated CCA cells were studied using a proteomic approach. To elucidate the possible mechanisms involved in the bile acid-mediated enhancement of CCA cell migration, the effects of six bile acids, including cholic, deoxycholic, taurocholic, taurodeoxycholic, glycocholic and glycodeoxycholic acid, on the migration of CCA cells were examined in vitro using wound healing assays. Subsequently, the possible proteins involved in enhanced CCA cell migration were investigated using a proteomic approach. Changes to the protein expression profiles of CCA cells following bile acid treatment was examined using two-dimensional electrophoresis and mass spectrometry. The results demonstrated that cholic and deoxycholic acid significantly enhanced the migration of CCA cells, compared with the treated MMNK-1 control cells. CCA cells had 77 overexpressed protein spots following cholic acid treatment, and 50 protein spots following deoxycholic acid treatment, compared with the treated MMNK-1 control cells. Liquid chromatography tandem-mass spectrometry analysis revealed that coiled-coil domain containing 25 (CCDC25) was significantly overexpressed in cholic acid-treated CCA cells compared with in cholic acid-treated control cells. When the expression levels of CCDC25 were investigated using western blot analysis, CCDC25 was demonstrated to be highly expressed in CCA tissues, but not in the adjacent non-cancerous tissue samples. The identified proteins were further analyzed for protein-chemical interactions using STITCH version 3.1 software. CCDC25 protein was identified to be associated with Son of sevenless homolog 1 and growth factor receptor-bound protein 2, which are involved in EGFR signaling. The results of the present study demonstrated that following cholic acid treatment, CCDC25 is overexpressed in CCA cells, which is associated with significantly enhanced cell migration. This suggests that CCDC25 is a potential therapeutic target for the treatment of patients with CCA.
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Affiliation(s)
- Siriporn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand.,Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Wachiraya Klinthong
- Centre of Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Tanakorn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand.,Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Temduang Limpaiboon
- Centre of Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand.,Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Patcharee Jearanaikoon
- Centre of Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand.,Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology, Pathumthani 12120, Thailand
| | - Chaisiri Wongkham
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Anongporn Nimboriboonporn
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sopit Wongkham
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
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23
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Sahu S, Sun W. Targeted therapy in biliary tract cancers-current limitations and potentials in the future. J Gastrointest Oncol 2017; 8:324-336. [PMID: 28480071 PMCID: PMC5401865 DOI: 10.21037/jgo.2016.09.16] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 08/17/2016] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancers (BTC)/Cholangiocarcinoma (CCA) is an aggressive biliary tract epithelial malignancy from varying locations within the biliary tree with cholangiocyte depreciation., including intrahepatic cholangiocarcinoma (iCCA) (iCCA), extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC). The disease is largely heterogeneous in etiology, epidemiology, and molecular profile. There are limited treatment options and low survival rates for those patients with advanced or metastatic disease. Systemic treatment is confined to cytotoxic chemotherapy with the combination of gemcitabine and cisplatin. Lack of a stereotype genetic signature makes difficult in identification of potential actionable target directly, which may also explain lack of obvious clinic benefit with target oriented agents from current studies. It is crucial to understand of BTC carcinogenesis, tumor-stroma interactions, and key molecular pathways, and herald to establish targeted, individualized therapies for the heterogeneous disease, and eventually to improve the survival and overall outcome of patients.
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Affiliation(s)
- Selley Sahu
- Division of Oncology, Department of Medicine Hematology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA
| | - Weijing Sun
- Division of Oncology, Department of Medicine Hematology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA
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Simone V, Brunetti O, Lupo L, Testini M, Maiorano E, Simone M, Longo V, Rolfo C, Peeters M, Scarpa A, Azzariti A, Russo A, Ribatti D, Silvestris N. Targeting Angiogenesis in Biliary Tract Cancers: An Open Option. Int J Mol Sci 2017; 18:418. [PMID: 28212293 PMCID: PMC5343952 DOI: 10.3390/ijms18020418] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/08/2017] [Accepted: 02/10/2017] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.
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Affiliation(s)
- Valeria Simone
- Operative Unit of Internal Medicine, Hospital "F.Ferrari", 73042 Casarano (Le), Italy.
| | - Oronzo Brunetti
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Luigi Lupo
- Department of Emergency and Organ Transplantation, Institute of General Surgery and Liver Transplantation, University of Bari, 70124 Bari, Italy.
| | - Mario Testini
- Department of Biomedical Sciences and Human Oncology, Unit of Endocrine, Digestive and Emergency Surgery, 70124 Bari, Italy.
| | - Eugenio Maiorano
- Department of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, "Aldo Moro" University, 70124 Bari, Italy.
| | - Michele Simone
- Surgical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Vito Longo
- Medical Oncology Unit, Hospital of Taranto, 74010 Taranto, Italy.
| | - Christian Rolfo
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital & Center for Oncological Research, 2650 Edegem, Belgium.
| | - Marc Peeters
- Oncology Department, Antwerp University Hospital, 2650 Edegem, Belgium.
| | - Aldo Scarpa
- ARC-NET (Applied Research on Cancer-Network) Research Centre, University of Verona, 37134 Verona, Italy.
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.
| | - Amalia Azzariti
- Preclinical and Clinical Pharmacology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90144 Palermo, Italy.
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.
- Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Nicola Silvestris
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
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Hammerling U, Bergman Laurila J, Grafström R, Ilbäck NG. Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association. Crit Rev Food Sci Nutr 2016; 56:614-34. [PMID: 25849747 DOI: 10.1080/10408398.2014.972498] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC.
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Affiliation(s)
- Ulf Hammerling
- a Cancer Pharmacology & Computational Medicine, Department of Medical Sciences, Uppsala University and Uppsala Academic Hospital , Uppsala , Sweden
| | - Jonas Bergman Laurila
- b Sahlgrenska Biobank, Gothia Forum, Sahlgrenska University Hospital , Gothenburg , Sweden
| | - Roland Grafström
- c Institute of Environmental Medicine, The Karolinska Institute , Stockholm , Sweden.,d Knowledge Intensive Products and Services, VTT Technical Research Centre of Finland , Turku , Finland
| | - Nils-Gunnar Ilbäck
- e Clinical Microbiology & Infectious Medicine, Department of Medical Sciences, Uppsala University and Uppsala Academic Hospital , Uppsala , Sweden
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Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. Cholangiocarcinoma. Crit Rev Oncol Hematol 2016; 116:11-31. [PMID: 28693792 DOI: 10.1016/j.critrevonc.2016.11.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 11/07/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.
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Affiliation(s)
| | - Luca Tondulli
- Medical Oncology Unit, Borgo Roma Hospital, Verona, Italy
| | - Gemma Gatta
- Italian National Cancer Institute, Milan, Italy
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22(R)-hydroxycholesterol induces HuR-dependent MAP kinase phosphatase-1 expression via mGluR5-mediated Ca(2+)/PKCα signaling. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:1056-70. [PMID: 27206966 DOI: 10.1016/j.bbagrm.2016.05.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/01/2016] [Accepted: 05/16/2016] [Indexed: 12/20/2022]
Abstract
MAP kinase phosphatase (MKP)-1 plays a pivotal role in controlling MAP kinase (MAPK)-dependent (patho) physiological processes. Although MKP-1 gene expression is tightly regulated at multiple levels, the underlying mechanistic details remain largely unknown. In this study, we demonstrate that MKP-1 expression is regulated at the post-transcriptional level by 22(R)-hydroxycholesterol [22(R)-HC] through a novel mechanism. 22(R)-HC induces Hu antigen R (HuR) phosphorylation, cytoplasmic translocation and binding to MKP-1 mRNA, resulting in stabilization of MKP-1 mRNA. The resulting increase in MKP-1 leads to suppression of JNK-mediated inflammatory responses in brain astrocytes. We further demonstrate that 22(R)-HC-induced phosphorylation of nuclear HuR is mediated by PKCα, which is activated in the cytosol by increases in intracellular Ca(2+) levels mediated by the phospholipase C/inositol 1,4,5-triphosphate receptor (PLC/IP3R) pathway and translocates from cytoplasm to nucleus. In addition, pharmacological interventions reveal that metabotropic glutamate receptor5 (mGluR5) is responsible for the increases in intracellular Ca(2+) that underlie these actions of 22(R)-HC. Collectively, our findings identify a novel anti-inflammatory mechanism of 22(R)-HC, which acts through PKCα-mediated cytoplasmic shuttling of HuR to post-transcriptionally regulate MKP-1 expression. These findings provide an experimental basis for the development of a RNA-targeted therapeutic agent to control MAPK-dependent inflammatory responses.
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28
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Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RIR, Raggi C, Perugorria MJ, Gaudio E, Boberg KM, Marin JJG, Alvaro D. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016; 13:261-80. [PMID: 27095655 DOI: 10.1038/nrgastro.2016.51] [Citation(s) in RCA: 942] [Impact Index Per Article: 104.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, Ikerbasque, CIBERehd, Paseo del Dr. Begiristain s/n, E-20014, San Sebastian, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro De Bosis 6, 00135, Rome, Italy
| | - Marco Marzioni
- Department of Clinic and Molecular Sciences, Polytechnic University of Marche, Via Tronto 10, 60020, Ancona, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark
| | - Pietro Invernizzi
- Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900, Monza, Italy
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway
| | - Trine Folseraas
- Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb. 4950 Nydalen, N-0424, Oslo, Norway
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, 49 Little France Crescent, EH16 4SB, Edinburgh, United Kingdom
| | - Laura Fouassier
- INSERM UMR S938, Centre de Recherche Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571, Paris cedex 12, Fondation ARC, 9 rue Guy Môquet 94803 Villejuif, France
| | - Andreas Geier
- Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstrasse 6, D-97080, Würzburg, Germany
| | - Diego F Calvisi
- Institute of Pathology, Universitätsmedizin Greifswald, Friedrich-Löffler-Strasse 23e, 17489, Greifswald, Germany
| | - Joachim C Mertens
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091, Zürich, Switzerland
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | - Antonio Benedetti
- Department of Clinic and Molecular Sciences, Polytechnic University of Marche, Via Tronto 10, 60020, Ancona, Italy
| | - Luca Maroni
- Department of Clinic and Molecular Sciences, Polytechnic University of Marche, Via Tronto 10, 60020, Ancona, Italy
| | - Javier Vaquero
- INSERM UMR S938, Centre de Recherche Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571, Paris cedex 12, Fondation ARC, 9 rue Guy Môquet 94803 Villejuif, France
| | - Rocio I R Macias
- Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Campus Miguel de Unamuno, E.I.D. S-09, University of Salamanca, IBSAL, CIBERehd, 37007, Salamanca, Spain
| | - Chiara Raggi
- Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, Ikerbasque, CIBERehd, Paseo del Dr. Begiristain s/n, E-20014, San Sebastian, Spain
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50, 00161, Rome, Italy
| | - Kirsten M Boberg
- Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb. 4950 Nydalen, N-0424, Oslo, Norway
| | - Jose J G Marin
- Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Campus Miguel de Unamuno, E.I.D. S-09, University of Salamanca, IBSAL, CIBERehd, 37007, Salamanca, Spain
| | - Domenico Alvaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
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Ilyas SI, Eaton JE, Gores GJ. Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management. Clin Gastroenterol Hepatol 2015; 13:2152-65. [PMID: 26051390 PMCID: PMC4618039 DOI: 10.1016/j.cgh.2015.05.035] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/20/2015] [Accepted: 05/22/2015] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John E Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Rojas-Caraballo J, López-Abán J, Fernández-Soto P, Vicente B, Collía F, Muro A. Gene Expression Profile in the Liver of BALB/c Mice Infected with Fasciola hepatica. PLoS One 2015; 10:e0134910. [PMID: 26247779 PMCID: PMC4527836 DOI: 10.1371/journal.pone.0134910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 07/15/2015] [Indexed: 01/21/2023] Open
Abstract
Background Fasciola hepatica infection still remains one of the helminthic neglected tropical diseases (NTDs). It has a huge worldwide distribution, affecting mainly cattle and, sometimes, human beings. In addition to data reported about the immunological response induced by helminthic infections and that induced by Fasciola hepatica, little is known about the gene expression profile in its organ target, the liver, which is where adult worms are established and live for long periods of time, causing its characteristic pathology. In the present work, we study both the early and late gene expression profiles in the livers of mice infected with F. hepatica metacercariae using a microarray-based methodology. Methodology A total of 9 female-6-week-old BALB/c mice (Charles River Laboratories, Barcelona, Spain) weighing 20 to 35 g were used for the experiments. Two groups of BALB/c mice were orally infected with seven F. hepatica metacercariae, and the other group remained untreated and served as a control. Mice were humanely euthanized and necropsied for liver recovery, histological assessment of hepatic damage, RNA isolation, microarray design and gene expression analysis on the day of infection (t0), seven days post-infection (t7) and twenty-one days post-infection (t21). Results We found that F. hepatica infection induces the differential expression of 128 genes in the liver in the early stage of infection and 308 genes in the late stage, and most of them are up-regulated. The Ingenuity Pathway Analysis revealed significant changes in the pathways related to metabolism, biosynthesis and signaling as well as genes implicated in inducing liver-toxicity, injury and death. Conclusion The present study provides us insights at the molecular level about the underlying mechanisms used by F. hepatica, leading to liver damage and its subsequent pathophysiology. The expression pattern obtained here could also be used to explain the lack of association between infection with F. hepatica and cholangiocarcinoma. However, more studies should be performed to confirm this hypothesis.
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Affiliation(s)
- Jose Rojas-Caraballo
- Instituto de Investigación Biomédica de Salamanca—Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (IBSAL-CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Castilla y León, España
| | - Julio López-Abán
- Instituto de Investigación Biomédica de Salamanca—Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (IBSAL-CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Castilla y León, España
| | - Pedro Fernández-Soto
- Instituto de Investigación Biomédica de Salamanca—Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (IBSAL-CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Castilla y León, España
| | - Belén Vicente
- Instituto de Investigación Biomédica de Salamanca—Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (IBSAL-CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Castilla y León, España
| | - Francisco Collía
- Departamento de Anatomía e Histología Humanas, Facultad de Medicina, Universidad de Salamanca, Salamanca, Castilla y León, España
| | - Antonio Muro
- Instituto de Investigación Biomédica de Salamanca—Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (IBSAL-CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Castilla y León, España
- * E-mail:
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Yao L, Han C, Song K, Zhang J, Lim K, Wu T. Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer Res 2015; 75:1388-98. [PMID: 25691459 DOI: 10.1158/0008-5472.can-14-2561] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 01/26/2015] [Indexed: 12/19/2022]
Abstract
Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its inactivation. Therefore, 15-PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here, we report that omega-3 polyunsaturated fatty acids (ω-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to ω-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH enzymes levels, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miR-26a and miR-26b, which target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ω-3 PUFA suppressed miR-26a and miR-26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of ω-3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for ω-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ω-3 PUFA in treatment of this malignancy.
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Affiliation(s)
- Lu Yao
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyu Lim
- Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling, Network Research Center, Chungnam National University, Daejeon, Korea
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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Oxidative stress and its significant roles in neurodegenerative diseases and cancer. Int J Mol Sci 2014; 16:193-217. [PMID: 25547488 PMCID: PMC4307243 DOI: 10.3390/ijms16010193] [Citation(s) in RCA: 305] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 12/05/2014] [Indexed: 02/07/2023] Open
Abstract
Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizing carbonylated proteins reveal oxidative damage to heat shock proteins in neurodegenerative disease models and inflammation-related cancer, suggesting dysfunction in their antioxidative properties. In neurodegenerative diseases, DNA damage may not only play a role in the induction of apoptosis, but also may inhibit cellular division via telomere shortening. Immunohistochemical analyses showed co-localization of oxidative/nitrative DNA lesions and stemness markers in the cells of inflammation-related cancers. Here, we review oxidative stress and its significant roles in neurodegenerative diseases and cancer.
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Zarrouk A, Vejux A, Mackrill J, O’Callaghan Y, Hammami M, O’Brien N, Lizard G. Involvement of oxysterols in age-related diseases and ageing processes. Ageing Res Rev 2014; 18:148-62. [PMID: 25305550 DOI: 10.1016/j.arr.2014.09.006] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 09/23/2014] [Accepted: 09/30/2014] [Indexed: 12/15/2022]
Abstract
Ageing is accompanied by increasing vulnerability to major pathologies (atherosclerosis, Alzheimer's disease, age-related macular degeneration, cataract, and osteoporosis) which can have similar underlying pathoetiologies. All of these diseases involve oxidative stress, inflammation and/or cell death processes, which are triggered by cholesterol oxide derivatives, also named oxysterols. These oxidized lipids result either from spontaneous and/or enzymatic oxidation of cholesterol on the steroid nucleus or on the side chain. The ability of oxysterols to induce severe dysfunctions in organelles (especially mitochondria) plays key roles in RedOx homeostasis, inflammatory status, lipid metabolism, and in the control of cell death induction, which may at least in part contribute to explain the potential participation of these molecules in ageing processes and in age related diseases. As no efficient treatments are currently available for most of these diseases, which are predicted to become more prevalent due to the increasing life expectancy and average age, a better knowledge of the biological activities of the different oxysterols is of interest, and constitutes an important step toward identification of pharmacological targets for the development of new therapeutic strategies.
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Abstract
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.
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Affiliation(s)
- Sumera Rizvi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Mitesh J. Borad
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona
| | - Tushar Patel
- Departments of Internal Medicine, Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Abstract
It has become increasingly apparent of late that inflammation plays an integral role in a spectrum of malignancies including cholangiocarcinoma (CCA). Primary sclerosing cholangitis with chronic inflammation is the most common risk factor for CCA in the Western world. Recent work has highlighted that inflammatory pathways are essential in carcinogenesis and tissue invasion and migration. Inflammation advances carcinogenesis by induction of DNA damage, evasion of apoptosis, promotion of cell proliferation, and neoangiogenesis. CCA is characterized by the presence of a desmoplastic stroma consisting of cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating lymphocytes. This rich inflammatory milieu is vital to the cancer ecosystem, and targeting its components represents an attractive therapeutic option.
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Affiliation(s)
- Sumera Rizvi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn., USA
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Ilyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145:1215-29. [PMID: 24140396 PMCID: PMC3862291 DOI: 10.1053/j.gastro.2013.10.013] [Citation(s) in RCA: 951] [Impact Index Per Article: 79.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 10/08/2013] [Accepted: 10/10/2013] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Jusakul A, Loilome W, Namwat N, Techasen A, Kuver R, Ioannou G, Savard C, Haigh WG, Yongvanit P. Anti-apoptotic phenotypes of cholestan-3β,5α,6β-triol-resistant human cholangiocytes: characteristics contributing to the genesis of cholangiocarcinoma. J Steroid Biochem Mol Biol 2013; 138:368-75. [PMID: 23959098 PMCID: PMC3825754 DOI: 10.1016/j.jsbmb.2013.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 07/29/2013] [Accepted: 08/06/2013] [Indexed: 12/30/2022]
Abstract
The oxysterols cholestan-3β,5α,6β-triol (Triol) and 3-keto-cholest-4-ene (3K4) are increased in Opisthorchis viverrini-associated hamster cholangiocarcinoma and induce DNA damage and apoptosis via a mitochondria-dependent mechanism in MMNK-1 human cholangiocytes. Based on these observations, we hypothesized that chronic exposure of cholangiocytes to these pathogenic oxysterols may allow a growth advantage to a subset of these cells through selection for resistance to apoptosis, thereby contributing to cholangiocarcinogenesis. To test this hypothesis, we cultured MMNK-1 cells long-term in the presence of Triol. Alteration in survival and apoptotic factors of Triol-exposed cells were examined. Cells cultured long-term in the presence of Triol were resistant to H2O2-induced apoptosis, and demonstrated an increase in the phosphorylation of p38-α, CREB, ERK1/2 and c-Jun. Elevations in the ratio of Bcl-2/Bax and in the protein levels of anti-apoptotic factors including cIAP2, clusterin, and survivin were detected. These results show that long-term exposure of MNNK-1 cells to low doses of Triol selects for kinase-signaling molecules which regulate resistance to apoptosis and thereby enhance cell survival. Clonal expansion of such apoptosis-resistant cells may contribute to the genesis of cholangiocarcinoma.
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Affiliation(s)
- Apinya Jusakul
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Anchalee Techasen
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Rahul Kuver
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - George Ioannou
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Christopher Savard
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - W. Geoffrey Haigh
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Puangrat Yongvanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Corresponding author: Puangrat Yongvanit, Ph.D., Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Phone: +66(43)-348386, Fax: +66(43)-348386,
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Zabron A, Edwards RJ, Khan SA. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Dis Model Mech 2013; 6:281-92. [PMID: 23520144 PMCID: PMC3597011 DOI: 10.1242/dmm.010561] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field.
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Affiliation(s)
- Abigail Zabron
- Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, St Mary's Hospital Campus, South Wharf Road, London, W2 1NY, UK.
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Dai J, Wang H, Dong Y, Zhang Y, Wang J. Bile acids affect the growth of human cholangiocarcinoma via NF-kB pathway. Cancer Invest 2013; 31:111-120. [PMID: 23362950 DOI: 10.3109/07357907.2012.762781] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We observed that free bile acids (CA, DCA, and CDCA) inhibited the growth of cholangiocarcinoma cells by promoting cell apoptosis, while the conjugated bile acids (GCA, GDCA, and GCDCA) stimulated cell growth. Consistently, we found that GDCA stimulated tumor growth and CDCA decreased tumor growth in xenografted mice. Further, the phosphorylated IkB was downregulated by free bile acids, and was upregulated by the conjugated bile acids. IL-6 and COX-2 were decreased by the free bile acids and increased by the conjugated bile acids. Collectively, these results suggest that the bile acids regulate the growth of cholangiocarcinoma by modulating NF-kB pathway.
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Affiliation(s)
- Jiaqi Dai
- Divisions of General Surgery, Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Kuver R. Mechanisms of oxysterol-induced disease: insights from the biliary system. CLINICAL LIPIDOLOGY 2012; 7:537-548. [PMID: 23630545 PMCID: PMC3636558 DOI: 10.2217/clp.12.53] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Oxysterols are oxidized species of cholesterol that are derived from exogenous (e.g. dietary) and endogenous (in vivo) sources. Oxysterols play critical roles in normal physiologic functions as well as in pathophysiologic processes in a variety of organ systems. This review provides an overview of oxysterol biology from the vantage point of the biliary system. Several oxysterols have been identified in human bile in the context of biliary tract infection and inflammation. This finding has led to investigations regarding the potential pathophysiologic significance of biliary oxysterols in diseases affecting the biliary system, with an emphasis on cholangiocarcinoma. Emerging evidence implicates specific oxysterols in the development and progression of this malignancy. This review will summarize the literature on oxysterols in the biliary system and discuss how the accumulated evidence contributes to a hypothesis describing the molecular basis of cholangiocarcinogenesis.
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Affiliation(s)
- Rahul Kuver
- Division of Gastroenterology, Box 356424, Department of Medicine, University of Washington School of Medicine, 1959 Northeast Pacific Street, Seattle, WA 98195, USA, Tel.: +1 206 543 1305, ,
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Calderón-Santiago M, Peralbo-Molina Á, Priego-Capote F, Luque de Castro MD. Cholesterol oxidation products in milk: Processing formation and determination. EUR J LIPID SCI TECH 2012. [DOI: 10.1002/ejlt.201100139] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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43
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Lee CC, Huang SH, Yang YT, Cheng YW, Li CH, Kang JJ. Motorcycle exhaust particles up-regulate expression of vascular adhesion molecule-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells. Toxicol In Vitro 2012; 26:552-60. [DOI: 10.1016/j.tiv.2012.01.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 12/01/2011] [Accepted: 01/23/2012] [Indexed: 10/14/2022]
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Vicente SJV, Sampaio GR, Ferrari CKB, Torres EAFS. Oxidation of Cholesterol in Foods and Its Importance for Human Health. FOOD REVIEWS INTERNATIONAL 2012. [DOI: 10.1080/87559129.2011.594972] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Abstract
Epidemiological data from the last years show an increasing trend of incidence and mortality of cholangiocarcinoma (CC) worldwide. Many pathophysiologic aspects of this neoplasia are still unknown and need to be fully discovered. However, several progresses were recently made in order to establish the molecular mechanisms involved in the transformation and growth of malignant cholangiocytes. The principal concept that at least seems to be established is that cholangiocarcinogenesis is a multistep cellular process evolving from a normal condition of the epithelial biliary cells through a chronic inflammation status ending with malignant transformation. The bad prognosis related to CC justifies why a better identification of the molecular mechanisms involved in the growth and progression of this cancer is required for the development of effective preventive measures and valid treatment regimens. This Paper describes the scientific progresses made in the last years in defining the molecular pathways implicated in the generation of this devastating disease.
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Jusakul A, Loilome W, Namwat N, Haigh WG, Kuver R, Dechakhamphu S, Sukontawarin P, Pinlaor S, Lee SP, Yongvanit P. Liver fluke-induced hepatic oxysterols stimulate DNA damage and apoptosis in cultured human cholangiocytes. Mutat Res 2011; 731:48-57. [PMID: 22044627 DOI: 10.1016/j.mrfmmm.2011.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 10/12/2011] [Accepted: 10/18/2011] [Indexed: 12/12/2022]
Abstract
Oxysterols are cholesterol oxidation products that are generated by enzymatic reactions through cytochrome P450 family enzymes or by non-enzymatic reactions involving reactive oxygen and nitrogen species. Oxysterols have been identified in bile in the setting of chronic inflammation, suggesting that biliary epithelial cells are chronically exposed to these compounds in certain clinical settings. We hypothesized that biliary oxysterols resulting from liver fluke infection participate in cholangiocarcinogenesis. Using gas chromatography/mass spectrometry, we identified oxysterols in livers from hamsters infected with Opisthorchis viverrini that develop cholangiocarcinoma. Five oxysterols were found: 7-keto-cholesta-3,5-diene (7KD), 3-keto-cholest-4-ene (3K4), 3-keto-cholest-7-ene (3K7), 3-keto-cholesta-4,6-diene (3KD), and cholestan-3β,5α,6β-triol (Triol). Triol and 3K4 were found at significantly higher levels in the livers of hamsters with O. viverrini-induced cholangiocarcinoma. We therefore investigated the effects of Triol and 3K4 on induction of cholangiocarcinogenesis using an in vitro human cholangiocyte culture model. Triol- and 3K4-treated cells underwent apoptosis. Western blot analysis showed significantly increased levels of Bax and decreased levels of Bcl-2 in these cells. Increased cytochrome c release from mitochondria was found following treatment with Triol and 3K4. Triol and 3K4 also induced formation of the DNA adducts 1,N(6)-etheno-2'-deoxyadenosine, 3,N(4)-etheno-2'-deoxycytidine and 8-oxo-7,8-dihydro-2'-deoxyguanosine in cholangiocytes. The data suggest that Triol and 3K4 cause DNA damage via oxidative stress. Chronic liver fluke infection increases production of the oxysterols Triol and 3K4 in the setting of chronic inflammation in the biliary system. These oxysterols induce apoptosis and DNA damage in cholangiocytes. Insufficient and impaired DNA repair of such mutated cells may enhance clonal expansion and further drive the change in cellular phenotype from normal to malignant.
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Affiliation(s)
- Apinya Jusakul
- Department of Biochemistry, Khon Kaen University, Khon Kaen, Thailand
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Jusakul A, Yongvanit P, Loilome W, Namwat N, Kuver R. Mechanisms of oxysterol-induced carcinogenesis. Lipids Health Dis 2011; 10:44. [PMID: 21388551 PMCID: PMC3061933 DOI: 10.1186/1476-511x-10-44] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 03/09/2011] [Indexed: 12/28/2022] Open
Abstract
Oxysterols are oxidation products of cholesterol that are generated by enzymatic reactions mediated by cytochrome P450 family enzymes or by non-enzymatic reactions involving reactive oxygen and nitrogen species. Oxysterols play various regulatory roles in normal cellular processes such as cholesterol homeostasis by acting as intermediates in cholesterol catabolism. Pathological effects of oxysterols have also been described, and various reports have implicated oxysterols in several disease states, including atherosclerosis, neurological disease, and cancer. Numerous studies show that oxysterols are associated with various types of cancer, including cancers of the colon, lung, skin, breast and bile ducts. The molecular mechanisms whereby oxysterols contribute to the initiation and progression of cancer are an area of active investigation. This review focuses on the current state of knowledge regarding the role of oxysterols in carcinogenesis. Mutagenicity of oxysterols has been described in both nuclear and mitochondrial DNA. Certain oxysterols such as cholesterol-epoxide and cholestanetriol have been shown to be mutagenic and genotoxic. Oxysterols possess pro-oxidative and pro-inflammatory properties that can contribute to carcinogenesis. Oxysterols can induce the production of inflammatory cytokines such as interleukin-8 and interleukin-1β. Certain oxysterols are also involved in the induction of cyclo-oxygenase-2 expression. Inflammatory effects can also be mediated through the activation of liver-X-receptor, a nuclear receptor for oxysterols. Thus, several distinct molecular mechanisms have been described showing that oxysterols contribute to the initiation and progression of cancers arising in various organ systems.
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Affiliation(s)
- Apinya Jusakul
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Khaen, Thailand
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Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, Gentile R, Alvaro D. Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors. World J Gastrointest Oncol 2010; 2:407-16. [PMID: 21160904 PMCID: PMC3000454 DOI: 10.4251/wjgo.v2.i11.407] [Citation(s) in RCA: 137] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Revised: 11/04/2010] [Accepted: 11/11/2010] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary tree. CCA is currently classified as intra-hepatic or extra-hepatic CCA (EH-CCA). Recent evidences suggest that intra-hepatic CCA (IH-CCA) and EH-CCA are biologically different cancers, giving further support to a number of recent epidemiological studies showing large differences in terms of incidence, mortality and risk factors. The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH- with EH-CCA.
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Affiliation(s)
- Vincenzo Cardinale
- Vincenzo Cardinale, Rossella Semeraro, Alessia Torrice, Manuela Gatto, Cristina Napoli, Maria Consiglia Bragazzi, Raffaele Gentile, Domenico Alvaro, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza University of Rome, 00185 Rome, Italy
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Leelawat K, Udomchaiprasertkul W, Narong S, Leelawat S. Induction of MKP-1 prevents the cytotoxic effects of PI3K inhibition in hilar cholangiocarcinoma cells. J Cancer Res Clin Oncol 2010; 136:1537-44. [PMID: 20145951 DOI: 10.1007/s00432-010-0811-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2009] [Accepted: 01/28/2010] [Indexed: 12/22/2022]
Abstract
PURPOSE Hilar cholangiocarcinoma (Klatskin tumor) is one of the most difficult cancers to treat. We demonstrate activation of phosphoinositide-3-kinase (PI3K)/Akt signaling, which is a critical pathway for cell survival, in hilar cholangiocarcinoma cells. However, inhibition of PI3K has little effect on hilar cholangiocarcinoma cell survival. In this study, we investigated the mechanism by which hilar cholangiocarcinoma cells resist PI3K inhibitors. METHODS Human hilar cholangiocarcinoma cells KKU-100 were treated with PI3K inhibitors, and cell viability and apoptosis assays were performed. The expression of a MAPK phosphatase (MKP-1) that contributes to cancer cell survival in response to multiple stress stimuli was assayed by quantitative real-time RT-PCR and western blotting. In addition, the effects of the MKP-1 inhibitor were studied in KKU-100 cells treated with PI3K inhibitors. RESULTS Incubation of KKU-100 cells with PI3K inhibitors resulted in increased expression of MKP-1. Furthermore, we found that inhibition of MKP-1 using siRNA silencing sensitized KKU-100 cells to PI3K inhibitor-induced apoptosis via increased phosphorylation of p38 MAPK. CONCLUSIONS These results indicate that concurrent inhibition of PI3K and MKP-1 induces apoptosis in KKU-100 cells. Simultaneous targeting of the PI3K pathway and MKP-1 may be a useful approach to improve therapies directed against hilar cholangiocarcinoma.
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Affiliation(s)
- Kawin Leelawat
- Department of Surgery, Rajavithi Hospital, Bangkok, Thailand.
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50
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Liao PL, Cheng YW, Li CH, Wang YT, Kang JJ. 7-Ketocholesterol and cholesterol-5α,6α-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways. Toxicol Lett 2010; 197:88-96. [DOI: 10.1016/j.toxlet.2010.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 04/10/2010] [Accepted: 05/04/2010] [Indexed: 12/28/2022]
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