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Guest RV, Goeppert B, Nault JC, Sia D. Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:345-361. [PMID: 39341365 PMCID: PMC11841493 DOI: 10.1016/j.ajpath.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 10/01/2024]
Abstract
Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.
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Affiliation(s)
- Rachel V Guest
- Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Benjamin Goeppert
- Institute of Pathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Team "Functional Genomics of Solid Tumors", Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France; Liver Unit, Avicenne Hospital, APHP, University Sorbonne Paris Nord, Bobigny, France
| | - Daniela Sia
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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Putatunda V, Jusakul A, Roberts L, Wang XW. Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:362-377. [PMID: 39532242 PMCID: PMC11841490 DOI: 10.1016/j.ajpath.2024.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.
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Affiliation(s)
- Vijay Putatunda
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Lewis Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Xin Wei Wang
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Cooley MA, Schneider AR, Fritcher EGB, Milosevic D, Levy MJ, Bridgeman AR, Martin JA, Petersen BT, Dayyeh BKA, Storm AC, Law RJ, Vargas EJ, Garimella V, Zemla T, Jenkins SM, Yin J, Gores GJ, Roberts LR, Kipp BR, Chandrasekhara V. Utility of methylated DNA markers for the diagnosis of malignant biliary strictures. Hepatology 2025; 81:453-464. [PMID: 38905442 PMCID: PMC11827039 DOI: 10.1097/hep.0000000000000970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/24/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND AND AIMS Early identification of malignant biliary strictures (MBSs) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography. We aimed to evaluate the use of methylated DNA markers (MDMs) from biliary brushings to enhance MBS detection in a prospective cohort. APPROACH Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific droplet digital polymerase chain reaction. Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. RESULTS Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top 4 MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2%-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescence in situ hybridization (FISH). CONCLUSIONS The selected MDMs demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.
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Affiliation(s)
- Matthew A. Cooley
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota
| | - Amber R. Schneider
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Dragana Milosevic
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Michael J. Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Amber R. Bridgeman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - John A. Martin
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Bret T. Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Andrew C. Storm
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ryan J. Law
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Eric J. Vargas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vishal Garimella
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tyler Zemla
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Sarah M. Jenkins
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Jun Yin
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Benjamin R. Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Mayr C, Kiesslich T, Bekric D, Beyreis M, Kittl M, Ablinger C, Neureiter E, Pichler M, Prinz F, Ritter M, Neureiter D, Jakab M, Dobias H. Ouabain at nanomolar concentrations is cytotoxic for biliary tract cancer cells. PLoS One 2023; 18:e0287769. [PMID: 37390071 PMCID: PMC10312999 DOI: 10.1371/journal.pone.0287769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/31/2023] [Indexed: 07/02/2023] Open
Abstract
Biliary tract cancer is a deadly disease with limited therapeutic options. Ouabain is a well-known inhibitor of the pumping function of Na+/K+-ATPase, though there is evidence that low concentrations of ouabain lead to a reduction of cell viability of cancer cells independent of its inhibition of the pumping function of the Na+/K+-ATPase. Regarding the impact of ouabain on biliary tract cancer, no data is currently available. Therefore, we aimed for a first-time investigation of ouabain as a potential anti-neoplastic biliary tract cancer agent using comprehensive human biliary tract cancer in vitro models. We found that ouabain has a strong cell line-dependent cytotoxic effect with IC50 levels in the (low) nanomolar-range and that this effect was not associated with the mRNA expression levels of the Na+/K+-ATPase α, β and fxyd-subunits. Regarding the mode of cytotoxicity, we observed induction of apoptosis in biliary tract cancer cells upon treatment with ouabain. Interestingly, cytotoxic effects of ouabain at sub-saturating (< μM) levels were independent of cellular membrane depolarization and changes in intracellular sodium levels. Furthermore, using a 3D cell culture model, we found that ouabain disturbs spheroid growth and reduces the viability of biliary tract cancer cells within the tumor spheroids. In summary, our data suggest that ouabain possesses anti-biliary tract cancer potential at low μM-concentration in 2D and 3D in vitro biliary tract cancer models and encourage further detailed investigation.
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Affiliation(s)
- Christian Mayr
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, University Clinics Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Tobias Kiesslich
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, University Clinics Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Dino Bekric
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Marlena Beyreis
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Michael Kittl
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
- Translational Oncology, University Hospital of Augsburg, Augsburg, Germany
| | - Celina Ablinger
- Institute of Pharmacy, Paracelsus Medical University, Salzburg, Austria
| | - Elen Neureiter
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Research Unit for Non-Coding RNA and Genome Editing, Medical University of Graz, Graz, Austria
- Translational Oncology, University Hospital of Augsburg, Augsburg, Germany
| | - Felix Prinz
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Research Unit for Non-Coding RNA and Genome Editing, Medical University of Graz, Graz, Austria
| | - Markus Ritter
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
- Ludwig Boltzmann Institute for Arthritis und Rehabilitation, Paracelsus Medical University, Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, Salzburg, Austria
- Kathmandu University School of Medical Sciences, Dhulikhel, Nepal
| | - Daniel Neureiter
- Institute of Pathology, University Clinics Salzburg, Paracelsus Medical University, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Martin Jakab
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
- Ludwig Boltzmann Institute for Arthritis und Rehabilitation, Paracelsus Medical University, Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, Salzburg, Austria
| | - Heidemarie Dobias
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology Salzburg, Paracelsus Medical University, Salzburg, Austria
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Testa U, Pelosi E, Castelli G. Cholangiocarcinoma: Molecular Abnormalities and Cells of Origin. Technol Cancer Res Treat 2023; 22:15330338221128689. [PMID: 36872875 PMCID: PMC9989414 DOI: 10.1177/15330338221128689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/01/2022] [Accepted: 09/07/2022] [Indexed: 03/07/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are a group of heterogeneous epithelial malignancies that can originate at the level of any location of the biliary tree. These tumors are relatively rare but associated with a high rate of mortality. CCAs are morphologically and molecularly heterogeneous and for their location can be distinguished as intracellular and extracellular, subdivided into perihilar and distal. Recent epidemiological, molecular, and cellular studies have supported that the consistent heterogeneity observed for CCAs may result from the convergence of various key elements mainly represented by risk factors, heterogeneity of the associated molecular abnormalities at genetic and epigenetic levels and by different potential cells of origin. These studies have consistently contributed to better defining the pathogenesis of CCAs and to identify in some instances new therapeutic targets. Although the therapeutic progress were still limited, these observations suggest that a better understanding of the molecular mechanisms underlying CCA in the future will help to develop more efficacious treatment strategies.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
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Harding JJ, Khalil DN, Fabris L, Abou-Alfa GK. Rational development of combination therapies for biliary tract cancers. J Hepatol 2023; 78:217-228. [PMID: 36150578 PMCID: PMC11111174 DOI: 10.1016/j.jhep.2022.09.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/06/2022] [Accepted: 09/08/2022] [Indexed: 02/01/2023]
Abstract
Biliary tract cancers are an uncommon set of gastrointestinal malignancies that are associated with high morbidity and mortality rates. Most patients present with incurable locally advanced or metastatic disease. The pathophysiology of biliary tract cancer can be exploited for direct therapeutic benefit, and indeed, chemotherapy, precision medicine, immunotherapy and combination treatments are now applied as both standard-of-care and investigational therapies. In the first-line setting, the immune-based chemotherapy combination of durvalumab plus gemcitabine and cisplatin has recently been shown to improve survival compared to chemotherapy alone. In the second-line, precision medicine can be employed in those with select genetic alterations in IDH1/2 (isocitrate dehydrogenase 1/2), FGFR2 (fibroblast growth factor receptor 2), KRAS, BRAF, ERBB2, NTRK (neurotrophic receptor tyrosine kinase), ROS, RET, and/or deficiencies in mismatch repair enzymes. In those patients without targetable genetic alterations, fluoropyridine doublets lead to modest improvements in outcomes. Next-generation sequencing is critical for direct patient care and to help elucidate genomic mechanisms of resistance in a research context. Currently, multiple clinical trials are ongoing - hence, this review seeks to provide an update on evolving standards of care and ongoing investigational agents, limitations to current treatments, and a framework for effective combination drug development for the future.
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Affiliation(s)
- James J Harding
- Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College at Cornell University, New York, NY, USA
| | - Danny N Khalil
- Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College at Cornell University, New York, NY, USA
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua, and Division of General Medicine, Padua University-Hospital, Padua, Italy; Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College at Cornell University, New York, NY, USA.
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FGFR Inhibitors in Cholangiocarcinoma-A Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next in Targeting This Axis? Cells 2022; 11:cells11233929. [PMID: 36497187 PMCID: PMC9737583 DOI: 10.3390/cells11233929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/20/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinomas (CCAs) are rare but aggressive tumours with poor diagnosis and limited treatment options. Molecular targeted therapies became a promising proposal for patients after progression under first-line chemical treatment. In light of an escalating prevalence of CCA, it is crucial to fully comprehend its pathophysiology, aetiology, and possible targets in therapy. Such knowledge would play a pivotal role in searching for new therapeutic approaches concerning diseases' symptoms and their underlying causes. Growing evidence showed that fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathway dysregulation is involved in a variety of processes during embryonic development and homeostasis as well as tumorigenesis. CCA is known for its close correlation with the FGF/FGFR pathway and targeting this axis has been proposed in treatment guidelines. Bearing in mind the significance of molecular targeted therapies in different neoplasms, it seems most reasonable to move towards intensive research and testing on these in the case of CCA. However, there is still a need for more data covering this topic. Although positive results of many pre-clinical and clinical studies are discussed in this review, many difficulties lie ahead. Furthermore, this review presents up-to-date literature regarding the outcomes of the latest clinical data and discussion over future directions of FGFR-directed therapies in patients with CCA.
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Wang Q, Qi Y, Xiong F, Wang D, Wang B, Chen Y. The H2A.Z-KDM1A complex promotes tumorigenesis by localizing in the nucleus to promote SFRP1 promoter methylation in cholangiocarcinoma cells. BMC Cancer 2022; 22:1166. [PMID: 36368958 PMCID: PMC9652970 DOI: 10.1186/s12885-022-10279-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC), originating from the bile ducts, is the second most common primary liver malignancy, and its incidence has recently increased. H2A.Z, a highly conserved H2A variant, is emerging as a key regulatory molecule in cancer. However, its underlying mechanism of action in ICC cells remains unclear. Methods Here, we examined the expression of H2A.Z and SFRP1 in normal intrahepatic cholangiocytes, ICC cell lines, ICC tissue microarrays, and fresh specimens. The correlations between H2A.Z or SFRP1 expression and clinical features were analysed. The overall survival rate was analysed based on H2A.Z and SFRP1 expression. Immunoprecipitation was used to analyse the recruitment of KDM1A, and ChIP sequencing and BSP were used to analyse the enrichment of methylation-related molecules such as H3K4me1 and H3K4me2 in the SFRP1 promoter and reveal the underlying mechanisms. Knockdown and rescue experiments were used to determine the potential mechanism by which H2A.Z and SFRP1 promote tumorigenesis in vitro. Results We showed that upregulation of H2A.Z expression is linked to downregulation of SFRP1 expression in ICC tissues and poor overall survival in patients with ICC. H2A.Z interacted with KDM1A in the nucleus to bind to the -151 ~ -136 bp region upstream of the SFRP1 promoter to increase its demethylation in ICC cells. Functionally, H2A.Z silencing inhibited the proliferation and invasion of ICC cells, and these effects were mitigated by SFRP1 silencing in ICC cells. Conclusions Our findings reveal that H2A.Z inhibits SFRP1 expression through chromatin modification in the context of ICC by forming a complex with KDM1A in the nucleus. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10279-y.
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Flanagan DJ, Woodcock SA, Phillips C, Eagle C, Sansom OJ. Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition. Pharmacol Ther 2022; 238:108179. [PMID: 35358569 PMCID: PMC9531712 DOI: 10.1016/j.pharmthera.2022.108179] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/20/2022]
Abstract
Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.
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Affiliation(s)
- Dustin J Flanagan
- Cancer Research UK Beatson Institute, Glasgow, UK; Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | | | | | | | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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Param NJ, Bramel ER, Sia D. The Molecular Pathogenesis and Targeted Therapies for Cholangiocarcinoma. Surg Pathol Clin 2022; 15:529-539. [PMID: 36049834 DOI: 10.1016/j.path.2022.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Cholangiocarcinoma (CCA) is a group of malignancies of the bile ducts with high mortality rates and limited treatment options. In the past decades, remarkable efforts have been dedicated toward elucidating the specific molecular signaling pathways and oncogenic loops driving cholangiocarcinogenesis to ultimately develop more effective therapies. Despite some recent advances, an extensive intra- and inter-tumor heterogeneity together with a poorly understood immunosuppressive microenvironment significantly compromises the efficacy of available treatments. Here, we provide a concise review of the latest advances and current knowledge of the molecular pathogenesis of CCA focusing on clinically relevant aberrations as well as future research avenues.
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Affiliation(s)
- Nesteene Joy Param
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA
| | - Emily R Bramel
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA
| | - Daniela Sia
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA.
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11
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Phillips C, Bhamra I, Eagle C, Flanagan E, Armer R, Jones CD, Bingham M, Calcraft P, Edmenson Cook A, Thompson B, Woodcock SA. The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand-dependent Cancer Models. CANCER RESEARCH COMMUNICATIONS 2022; 2:914-928. [PMID: 36922934 PMCID: PMC10010340 DOI: 10.1158/2767-9764.crc-21-0095] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 05/16/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022]
Abstract
Wnt signaling is implicated in the etiology of gastrointestinal tract cancers. Targeting Wnt signaling is challenging due to on-target toxicity concerns and lack of druggable pathway components. We describe the discovery and characterization of RXC004, a potent and selective inhibitor of the membrane-bound o-acyl transferase Porcupine, essential for Wnt ligand secretion. Absorption, distribution, metabolism, and excretion and safety pharmacology studies were conducted with RXC004 in vitro, and pharmacokinetic exposure assessed in vivo. RXC004 effects on proliferation and tumor metabolism were explored in genetically defined colorectal and pancreatic cancer models in vitro and in vivo. RXC004 effects on immune evasion were assessed in B16F10 immune "cold" and CT26 immune "hot" murine syngeneic models, and in human cell cocultures. RXC004 showed a promising pharmacokinetic profile, inhibited Wnt ligand palmitoylation, secretion, and pathway activation, and demonstrated potent antiproliferative effects in Wnt ligand-dependent (RNF43-mutant or RSPO3-fusion) colorectal and pancreatic cell lines. Reduced tumor growth and increased cancer cell differentiation were observed in SNU-1411 (RSPO3-fusion), AsPC1 and HPAF-II (both RNF43-mutant) xenograft models, with a therapeutic window versus Wnt homeostatic functions. Additional effects of RXC004 on tumor cell metabolism were confirmed in vitro and in vivo by glucose uptake and 18fluorodeoxyglucose-PET, respectively. RXC004 stimulated host tumor immunity; reducing resident myeloid-derived suppressor cells within B16F10 tumors and synergizing with anti-programmed cell death protein-1 (PD-1) to increase CD8+/regulatory T cell ratios within CT26 tumors. Moreover, RXC004 reversed the immunosuppressive effects of HPAF-II cells cocultured with human peripheral blood mononuclear cells, confirming the multiple anticancer mechanisms of this compound, which has progressed into phase II clinical trials. Significance Wnt pathway dysregulation drives many gastrointestinal cancers; however, there are no approved therapies that target the pathway. RXC004 has demonstrated the potential to block both tumor growth and tumor immune evasion in a genetically defined, clinically actionable subpopulation of Wnt ligand-dependent gastrointestinal cancers. The clinical utility of RXC004, and other Porcupine inhibitors, in such Wnt ligand-dependent cancers is currently being assessed in patient trials.
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Affiliation(s)
| | - Inder Bhamra
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom
| | - Catherine Eagle
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom
| | - Eimear Flanagan
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom
| | - Richard Armer
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom
| | | | - Matilda Bingham
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom.,Concept Life Sciences Ltd, Manchester, United Kingdom
| | - Peter Calcraft
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom.,Analytical Development, Flu-BPD, AstraZeneca PLC, Manchester, United Kingdom
| | - Alicia Edmenson Cook
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom.,Oncology Cell Therapy, GlaxoSmithKline PLC, London, United Kingdom
| | - Ben Thompson
- Redx Oncology Ltd, Redx Pharma PLC; Cheshire, United Kingdom.,In Vitro, RxCelerate Ltd, Cambridge, United Kingdom
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Zhang X, Li A, Wu J, Wu Y, Ma X, Liu Y, Chen Q, Zhang Y. Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer. ASIAN BIOMED 2022; 16:181-189. [PMID: 37551167 PMCID: PMC10321177 DOI: 10.2478/abm-2022-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background Dickkopf 2 (DKK2) plays an important role in multiple cancers. Its potential value in the clinical diagnosis of cervical cancer has remained unclear. Objectives To investigate the expression and promoter methylation levels of DKK2 in cervical cancer and their clinicopathological associations. Methods We used the Gene Expression Omnibus, Oncomine, Cancer Genome Atlas, and University of ALabama at Birmingham CANcer data analysis databases, reverse transcription-PCR, and methylation-specific PCR analysis to predict and examine the expression of DKK2 mRNA and DKK2 methylation levels in cell lines and cervical cancer tissues from 79 patients with cervical cancer and 63 with cervical precancerous lesions including 25 with low-grade squamous intraepithelial lesions (LSIL) and 38 patients with high-grade squamous intraepithelial lesions (HSIL). Results DKK2 mRNA expression was downregulated in all cancer cell lines and cervical cancer tissues, whereas hypermethylation of DKK2 was higher in cervical cancer tissue samples. DKK2 methylation in cervical cancer was significantly higher than that in HSIL (χ2 = 8.346, P = 0.004), whereas DKK2 methylation in HSIL was significantly higher than that in normal cervical samples (χ2 = 7.934, P = 0.005) and in LSIL samples (χ2 = 4.375, P = 0.037). DKK2 silencing caused by its promoter hypermethylation was confirmed by treatment with the methyltransferase inhibitor 5-Aza-dC in cell lines. Patients with lymph node metastasis exhibited increased promoter methylation frequency (χ2 = 5.239, P = 0.022) and low DKK2 mRNA expression (χ2 = 3.958, P = 0.047) compared with patients with no lymph node metastasis. Patients with high-risk human papillomavirus infection exhibited increased promoter methylation frequency (χ2 = 6.279, P = 0.015). Conclusions DKK2 epigenetic changes of DKK2 may play a key role in the development of cervical cancer, suggesting that DKK2 hypermethylation could be used as a triage test for screening, early diagnosis, or risk prediction of cervical cancer.
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Affiliation(s)
- Xian Zhang
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Aihua Li
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Jie Wu
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, Shandong266000, China
| | - Yu Wu
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Xiaoping Ma
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Yanjun Liu
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Qingfa Chen
- Institute of Tissue Engineering and Regenerative Medicine, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
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13
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Rogalska-Taranta M, Andersen JB. Involvement of Epigenomic Factors in Bile Duct Cancer. Semin Liver Dis 2022; 42:202-211. [PMID: 35738258 DOI: 10.1055/s-0042-1748188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer. Due to its often-silent manifestation, sporadic nature, and typically late clinical presentation, it remains difficult to diagnose and lacks effective nonsurgical therapeutic options. Extensive research aiming in understanding the mechanisms underlying this disease have provided strong evidence for the significance of epigenetics contributing to its onset, progression, and dissemination. This dysregulation in a myriad of signaling pathways, leading to malignancy, spans altered deoxyribonucleic acid and histone methylation, histone acetylation, and chromatin remodeling, as well as genetic modifications in essential genes controlling these epigenetic processes. An advantage to epigenetic modifications is that they, compared with mutations, are reversible and can partially be controlled by inhibiting the responsible enzymatic machinery. This opens novel possibilities for developing new treatment modalities with benefit for CCA patients.In this article, we have reviewed the current status of epigenome modifications described in CCA, including the role of posttranslational histone modifications and chromatin remodeling, as well as novel advances in treatment options.
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Affiliation(s)
- Magdalena Rogalska-Taranta
- Biotech Research & Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research & Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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14
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Goeppert B, Stichel D, Toth R, Fritzsche S, Loeffler MA, Schlitter AM, Neumann O, Assenov Y, Vogel MN, Mehrabi A, Hoffmann K, Köhler B, Springfeld C, Weichenhan D, Plass C, Esposito I, Schirmacher P, von Deimling A, Roessler S. Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis. Gut 2022; 71:391-401. [PMID: 33468537 PMCID: PMC8762040 DOI: 10.1136/gutjnl-2020-322983] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/21/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options. DESIGN We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling. RESULTS Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin. CONCLUSION Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany .,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Damian Stichel
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany,German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany,Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Reka Toth
- Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sarah Fritzsche
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Olaf Neumann
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Yassen Assenov
- Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Monika Nadja Vogel
- Diagnostic and Interventional Radiology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany,Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Katrin Hoffmann
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany,Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Bruno Köhler
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany,Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany,Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Germany
| | - Dieter Weichenhan
- Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christoph Plass
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany,Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Andreas von Deimling
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany,German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany,Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany .,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
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15
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Falcomatà C, Bärthel S, Ulrich A, Diersch S, Veltkamp C, Rad L, Boniolo F, Solar M, Steiger K, Seidler B, Zukowska M, Madej J, Wang M, Öllinger R, Maresch R, Barenboim M, Eser S, Tschurtschenthaler M, Mehrabi A, Roessler S, Goeppert B, Kind A, Schnieke A, Robles MS, Bradley A, Schmid RM, Schmidt-Supprian M, Reichert M, Weichert W, Sansom OJ, Morton JP, Rad R, Schneider G, Saur D. Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer. Cancer Discov 2021; 11:3158-3177. [PMID: 34282029 PMCID: PMC7612573 DOI: 10.1158/2159-8290.cd-21-0209] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/25/2021] [Accepted: 07/01/2021] [Indexed: 11/16/2022]
Abstract
Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts with the pancreas, where oncogenic Kras in concert with p53 loss is a key cancer driver. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor subtype. SIGNIFICANCE We used the first genetically engineered mouse model for extrahepatic bile duct carcinoma to identify cancer genes by genome-wide transposon-based mutagenesis screening. Thereby, we show that PI3K signaling output strength and p27Kip1 function are critical determinants for context-specific ECC formation. This article is highlighted in the In This Issue feature, p. 2945.
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Affiliation(s)
- Chiara Falcomatà
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Stefanie Bärthel
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Angelika Ulrich
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
| | - Sandra Diersch
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Christian Veltkamp
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Lena Rad
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Fabio Boniolo
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Myriam Solar
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Katja Steiger
- Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Barbara Seidler
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Magdalena Zukowska
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Joanna Madej
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Mingsong Wang
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Rupert Öllinger
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany
| | - Roman Maresch
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany
| | - Maxim Barenboim
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany
- Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München, School of Medicine, Munich, Germany
| | - Stefan Eser
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Markus Tschurtschenthaler
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Arianeb Mehrabi
- Department of Surgery, Universität Heidelberg, Heidelberg, Germany
| | | | | | - Alexander Kind
- Livestock Biotechnology, Technische Universität München, Freising, Germany
| | - Angelika Schnieke
- Livestock Biotechnology, Technische Universität München, Freising, Germany
| | - Maria S. Robles
- Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Allan Bradley
- Wellcome Trust Sanger Institute, Genome Campus, Hinxton-Cambridge, United Kingdom
| | - Roland M. Schmid
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Marc Schmidt-Supprian
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Experimental Hematology, School of Medicine, Technische Universität München, Munich, Germany
| | - Maximilian Reichert
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Center for Protein Assemblies (CPA), Technische Universität München, Garching, Germany
| | - Wilko Weichert
- Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Jennifer P. Morton
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Roland Rad
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany
| | - Günter Schneider
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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16
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Yosudjai J, Inpad C, Pothipan P, Saisomboon S, Surangkul D, Phimsen S, Hongsrichan N, Wongkham S, Jirawatnotai S, Roytrakul S, Kaewkong W. Overexpression of AGR2vH, an oncogenic AGR2 spliced transcript, potentiates tumorigenicity and proteomic alterations in cholangiocarcinoma cell. Biosci Biotechnol Biochem 2021; 85:2263-2273. [PMID: 34494080 DOI: 10.1093/bbb/zbab156] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/02/2021] [Indexed: 11/12/2022]
Abstract
The upregulation of anterior gradient 2 (AGR2) has been observed in cholangiocarcinoma (CCA) cells, nras-mutant zebrafish, and specimens derived from CCA patients. Our previous study reported AGR2 splicing into AGR2vH to facilitate CCA cell aggressiveness, while this work aims to investigate the molecular mechanisms underlying AGR2vH. First, AGR2vH upregulation was demonstrated in CCA tissues derived from patients. For in vitro studies, established AGR2vH-overexpressing KKU-213A cells were found to exhibit increased proliferation and clonogenicity. In vivo tumorigenicity assessed in a mouse model represented higher tumorigenic potential in AGR2vH-overexpressing cell xenograft mice. Next, LC-MS/MS was analyzed, indicating that AGR2vH may be associated with CCA cell proliferation via Wnt/β-catenin signaling pathway activation, which was verified by β-catenin expression and nuclear translocation. The current results provide evidence that AGR2vH upregulation promotes tumorigenicity in CCA cells linked with an alteration of CCA cell proteome.
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Affiliation(s)
- Juthamas Yosudjai
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Chaturong Inpad
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Phattarin Pothipan
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Saowaluk Saisomboon
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Damrasamon Surangkul
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Suchada Phimsen
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Nuttanan Hongsrichan
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center of Research for Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
| | - Worasak Kaewkong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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17
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Di-Luoffo M, Pirenne S, Saandi T, Loriot A, Gérard C, Dauguet N, Manzano-Núñez F, Alves Souza Carvalhais N, Lamoline F, Cordi S, Konobrocka K, De Greef V, Komuta M, Halder G, Jacquemin P, Lemaigre FP. A Mouse Model of Cholangiocarcinoma Uncovers a Role for Tensin-4 in Tumor Progression. Hepatology 2021; 74:1445-1460. [PMID: 33768568 DOI: 10.1002/hep.31834] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 03/05/2021] [Accepted: 03/14/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis. APPROACH AND RESULTS To this end, we generated a mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. We found that mice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs), and, eventually, iCCAs. The histology of mouse and human IPNBs was similar, and mouse iCCAs displayed histological characteristics of human mucin-producing, large-duct-type iCCA. Signaling pathways activated in human iCCA were also activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We further provide evidence that tensin-4 (TNS4), which is stimulated by KRASG12D and SRY-related HMG box transcription factor 17, promotes tumor progression. CONCLUSIONS We developed a mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade which involves TNS4 and promotes tumor progression.
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Affiliation(s)
- Mickaël Di-Luoffo
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Sophie Pirenne
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium.,Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Thoueiba Saandi
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Axelle Loriot
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Claude Gérard
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Nicolas Dauguet
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium.,CYTF Platform, Université catholique de Louvain, Brussels, Belgium
| | | | | | - Florence Lamoline
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Sabine Cordi
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | | | - Vitaline De Greef
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Mina Komuta
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Georg Halder
- VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
| | - Patrick Jacquemin
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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18
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Sato K, Baiocchi L, Kennedy L, Zhang W, Ekser B, Glaser S, Francis H, Alpini G. Current Advances in Basic and Translational Research of Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13133307. [PMID: 34282753 PMCID: PMC8269372 DOI: 10.3390/cancers13133307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Cholangiocarcinoma (CCA) is highly malignant biliary tract cancer, which is characterized by limited treatment options and poor prognosis. Basic science studies to seek therapies for CCA are also limited due to lack of gold-standard experimental models and heterogeneity of CCA resulting in various genetic alterations and origins of tumor cells. Recent studies have developed new experimental models and techniques that may facilitate CCA studies leading to the development of novel treatments. This review summarizes the update in current basic studies of CCA. Abstract Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are limited since early diagnosis is challenging, and the efficacy of chemotherapy or radiotherapy is also limited because CCA is a heterogeneous malignancy. Basic research is important for CCA to establish novel diagnostic testing and more effective therapies. Previous studies have introduced new techniques and methodologies for animal models, in vitro models, and biomarkers. Recent experimental strategies include patient-derived xenograft, syngeneic mouse models, and CCA organoids to mimic heterogeneous CCA characteristics of each patient or three-dimensional cellular architecture in vitro. Recent studies have identified various novel CCA biomarkers, especially non-coding RNAs that were associated with poor prognosis or metastases in CCA patients. This review summarizes current advances and limitations in basic and translational studies of CCA.
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Affiliation(s)
- Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.K.); (H.F.); (G.A.)
- Correspondence: ; Tel.: +1-317-278-4227
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Medicine, University of Tor Vergata, 00133 Rome, Italy;
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.K.); (H.F.); (G.A.)
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Wenjun Zhang
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (W.Z.); (B.E.)
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (W.Z.); (B.E.)
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA;
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.K.); (H.F.); (G.A.)
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.K.); (H.F.); (G.A.)
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
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19
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Lu X, Peng B, Chen G, Pes MG, Ribback S, Ament C, Xu H, Pal R, Rodrigues PM, Banales JM, Evert M, Calvisi DF, Chen X, Fan B, Wang J. YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1651-1667. [PMID: 34129844 DOI: 10.1016/j.ajpath.2021.05.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 05/24/2021] [Accepted: 05/27/2021] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway.
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Affiliation(s)
- Xinjun Lu
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
| | - Baogang Peng
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ge Chen
- University of Bristol, Bristol, United Kingdom
| | - Mario G Pes
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Silvia Ribback
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Cindy Ament
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Hongwei Xu
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California; Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Sichuan, China
| | - Rajesh Pal
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), ISCIII, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
| | - Biao Fan
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Jingxiao Wang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
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20
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Colyn L, Bárcena-Varela M, Álvarez-Sola G, Latasa MU, Uriarte I, Santamaría E, Herranz JM, Santos-Laso A, Arechederra M, Ruiz de Gauna M, Aspichueta P, Canale M, Casadei-Gardini A, Francesconi M, Carotti S, Morini S, Nelson LJ, Iraburu MJ, Chen C, Sangro B, Marin JJG, Martinez-Chantar ML, Banales JM, Arnes-Benito R, Huch M, Patino JM, Dar AA, Nosrati M, Oyarzábal J, Prósper F, Urman J, Cubero FJ, Trautwein C, Berasain C, Fernandez-Barrena MG, Avila MA. Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma. Hepatology 2021; 73:2380-2396. [PMID: 33222246 DOI: 10.1002/hep.31642] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 10/06/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. APPROACH AND RESULTS Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (JnkΔhepa + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in JnkΔhepa + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. CONCLUSIONS Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.
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Affiliation(s)
- Leticia Colyn
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
| | | | - Gloria Álvarez-Sola
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - M Ujue Latasa
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
| | - Iker Uriarte
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Eva Santamaría
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Jose M Herranz
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Ikerbasque, Donostia-San Sebastian, Spain
| | | | - Mikel Ruiz de Gauna
- Biocruces Health Research Institute, Department of Physiology, University of the Basque Country, Leioa, Spain
| | - Patricia Aspichueta
- Biocruces Health Research Institute, Department of Physiology, University of the Basque Country, Leioa, Spain
| | - Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University and Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Francesconi
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Simone Carotti
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy.,Predictive Molecular Diagnostic Division, Pathology Department, Campus Bio-Medico University Hospital, Rome, Italy
| | - Sergio Morini
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Leonard J Nelson
- School of Engineering, Institute of Engineering, The University of Edimburgh, Edimburgh, United Kingdom
| | - Maria J Iraburu
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain
| | - Chaobo Chen
- Department of Immunology, Ophtalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Bruno Sangro
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Hepatology Unit, Navarra University Clinic, Pamplona, Spain.,Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Jose J G Marin
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Maria L Martinez-Chantar
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CICbioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
| | - Jesus M Banales
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Ikerbasque, Donostia-San Sebastian, Spain
| | - Robert Arnes-Benito
- Max Plank Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Meritxell Huch
- Max Plank Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - John M Patino
- California Pacific Medical Center Research Institute, San Francisco, CA
| | - Altaf A Dar
- California Pacific Medical Center Research Institute, San Francisco, CA
| | - Mehdi Nosrati
- California Pacific Medical Center Research Institute, San Francisco, CA
| | - Julen Oyarzábal
- Molecular Therapies Program, CIMA, University of Navarra, Pamplona, Spain
| | - Felipe Prósper
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.,Oncohematology Program, CIMA, University of Navarra, Pamplona, Spain
| | - Jesus Urman
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.,Department of Digestive Diseases, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophtalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Carmen Berasain
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Maite G Fernandez-Barrena
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Matias A Avila
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
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21
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Brägelmann J, Barahona Ponce C, Marcelain K, Roessler S, Goeppert B, Gallegos I, Colombo A, Sanhueza V, Morales E, Rivera MT, de Toro G, Ortega A, Müller B, Gabler F, Scherer D, Waldenberger M, Reischl E, Boekstegers F, Garate-Calderon V, Umu SU, Rounge TB, Popanda O, Lorenzo Bermejo J. Epigenome-Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer. Hepatology 2021; 73:2293-2310. [PMID: 33020926 DOI: 10.1002/hep.31585] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH AND RESULTS To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine-guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. CONCLUSIONS Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.
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Affiliation(s)
- Johannes Brägelmann
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany.,Molecular Pathology, Institute of Pathology & Department of Translational Genomics, University Hospital of Cologne, Cologne, Germany.,Mildred Scheel School of Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany
| | - Carol Barahona Ponce
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany.,Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago, Chile
| | - Katherine Marcelain
- Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago, Chile
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ivan Gallegos
- Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago, Chile
| | - Alicia Colombo
- Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago, Chile.,Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago, Chile
| | - Verónica Sanhueza
- Servicio de Anatomía Patológica, Hospital Padre Hurtado, Santiago, Chile
| | - Erik Morales
- Facultad de Medicina, Universidad Catolica del Maule & Unidad de Anatomia Patologica del Hospital Regional de Talca, Talca, Chile
| | | | - Gonzalo de Toro
- Escuela de Tecnologia Medica, Universidad Austral de Chile sede Puerto Montt & Servicio de Anatomía Patológica, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Alejandro Ortega
- Servicio de Anatomía Patológica, Hospital Regional, Arica, Chile
| | - Bettina Müller
- Servicio de Oncología Médica, Instituto Nacional del Cáncer, Santiago, Chile
| | - Fernando Gabler
- Unidad de Anatomia Patologica, Hospital San Borja Arriaran, Santiago, Chile
| | - Dominique Scherer
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology and Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Eva Reischl
- Research Unit of Molecular Epidemiology and Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Felix Boekstegers
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany
| | - Valentina Garate-Calderon
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany.,Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago, Chile
| | - Sinan U Umu
- Department of Research, Cancer Registry of Norway, Oslo, Norway
| | - Trine B Rounge
- Department of Research, Cancer Registry of Norway, Oslo, Norway.,Department of Informatics, University of Oslo, Oslo, Norway
| | - Odilia Popanda
- Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany
| | - Justo Lorenzo Bermejo
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany
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22
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Yan Y, Zhang H, Gao S, Zhang H, Zhang X, Chen W, Lin W, Xie Q. Differential DNA Methylation and Gene Expression Between ALV-J-Positive and ALV-J-Negative Chickens. Front Vet Sci 2021; 8:659840. [PMID: 34136553 PMCID: PMC8203102 DOI: 10.3389/fvets.2021.659840] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/28/2021] [Indexed: 01/24/2023] Open
Abstract
Background: Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus that causes serious economic losses in the poultry industry; unfortunately, there is no effective vaccine against ALV-J. DNA methylation plays a crucial role in several biological processes, and an increasing number of diseases have been proven to be related to alterations in DNA methylation. In this study, we screened ALV-J-positive and -negative chickens. Subsequently, we generated and provided the genome-wide gene expression and DNA methylation profiles by MeDIP-seq and RNA-seq of ALV-J-positive and -negative chicken samples; 8,304 differentially methylated regions (DMRs) were identified by MeDIP-seq analysis (p ≤ 0.005) and 515 differentially expressed genes were identified by RNA-seq analysis (p ≤ 0.05). As a result of an integration analysis, we screened six candidate genes to identify ALV-J-negative chickens that possessed differential methylation in the promoter region. Furthermore, TGFB2 played an important role in tumorigenesis and cancer progression, which suggested TGFB2 may be an indicator for identifying ALV-J infections.
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Affiliation(s)
- Yiming Yan
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
| | - Huihua Zhang
- College of Life Science and Engineering, Foshan University, Foshan, China
| | - Shuang Gao
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
| | - Huanmin Zhang
- United States Department of Agriculture (USDA), Agriculture Research Service, Avian Disease and Oncology Laboratory, East Lansing, MI, United States
| | - Xinheng Zhang
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
| | - Weiguo Chen
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
| | - Wencheng Lin
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
| | - Qingmei Xie
- Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China.,South China Collaborative Innovation Center for Poultry Disease Control and Product Safety, Guangzhou, China
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23
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Cigliano A, Chen X, Calvisi DF. Current challenges to underpinning the genetic basis for cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:511-526. [PMID: 33888034 PMCID: PMC8173760 DOI: 10.1080/17474124.2021.1915128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/07/2021] [Indexed: 12/23/2022]
Abstract
AREAS COVERED This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype. EXPERT OPINION The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.
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Affiliation(s)
- Antonio Cigliano
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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24
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Bai X, Zhang H, Zhou Y, Nagaoka K, Meng J, Ji C, Liu D, Dong X, Cao K, Mulla J, Cheng Z, Mueller W, Bay A, Hildebrand G, Lu S, Wallace J, Wands JR, Sun B, Huang CK. Ten-Eleven Translocation 1 Promotes Malignant Progression of Cholangiocarcinoma With Wild-Type Isocitrate Dehydrogenase 1. Hepatology 2021; 73:1747-1763. [PMID: 32740973 PMCID: PMC7855500 DOI: 10.1002/hep.31486] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole-genome sequencing data indicate that about 20% of patients with CCA have isocitrate dehydrogenase 1 (IDH1) mutations, which have been suggested to target 2-oxoglutarate (OG)-dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that patients with CCA and mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. APPROACH AND RESULTS This study aimed to clarify if ten-eleven translocation 1 (TET1), which is one of the 2-OG-dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing The Cancer Genome Atlas (TCGA) data set, TET1 mRNA was found to be substantially up-regulated in patients with CCA when compared with noncancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG), which are cosubstrates for TET1 dioxygenase. The treatments with α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity, and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model by targeting cell growth and apoptosis. CONCLUSIONS Our data suggest that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate TET1 expression in CCA tumors before application of the IDH1 mutation inhibitor because the inhibitor suppresses 2-hydroxyglutarate expression, which may result in activation of TET, potentially leading to CCA malignancy.
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Affiliation(s)
- Xuewei Bai
- Department of Pancreatic and Biliary Surgery, First
Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Liver
Research Center, Division of Gastroenterology & Liver Research Center, Warren
Alpert Medical School of Brown University and Rhode Island Providence, RI, USA,Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Hongyu Zhang
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Yamei Zhou
- Department of Pancreatic and Biliary Surgery, First
Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Liver
Research Center, Division of Gastroenterology & Liver Research Center, Warren
Alpert Medical School of Brown University and Rhode Island Providence, RI, USA,Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Katsuya Nagaoka
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Jialin Meng
- Department of Urology, The First Affiliated Hospital of
Anhui Medical University; Institute of Urology & Anhui Province Key Laboratory
of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Chengcheng Ji
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Dan Liu
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Xianghui Dong
- Department of Pathology, The First Affiliated Hospital of
Harbin Medical University, Harbin 150001, Heilongjiang Province, P.R. China
| | - Kevin Cao
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Joud Mulla
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Zhixiang Cheng
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - William Mueller
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Amalia Bay
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Grace Hildebrand
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Shaolei Lu
- Department of Pathology and Laboratory Medicine, Warren
Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI,
USA
| | - Joselynn Wallace
- Center for Computational Biology of Human Disease and
Center for Computation and Visualization, Brown University, Providence, RI,
USA
| | - Jack R. Wands
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, First
Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Liver
Research Center, Division of Gastroenterology & Liver Research Center, Warren
Alpert Medical School of Brown University and Rhode Island Providence, RI, USA,Correspondence to: Chiung-Kuei Huang,
Ph.D., Liver Research Center, Rhode Island Hospital, Brown Alpert Medical
School, Brown University, 55 Claverick Street, Providence, RI 02903,
; Bei Sun, M.D., Ph.D. Department
of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin
Medical University. Key Laboratory of Hepatosplenic Surgery, Ministry of
Education, The First Affiliated Hospital of Harbin Medical University, No. 23
Youzheng Road, Nangang District, Harbin 150081, Heilongjiang Province, P.R.
China. Tel: 86-451-85555721; Fax: 86-451-53643849;
| | - Chiung-Kuei Huang
- Liver Research Center, Division of Gastroenterology &
Liver Research Center, Warren Alpert Medical School of Brown University and Rhode
Island Hospital, Providence, RI, USA,Correspondence to: Chiung-Kuei Huang,
Ph.D., Liver Research Center, Rhode Island Hospital, Brown Alpert Medical
School, Brown University, 55 Claverick Street, Providence, RI 02903,
; Bei Sun, M.D., Ph.D. Department
of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin
Medical University. Key Laboratory of Hepatosplenic Surgery, Ministry of
Education, The First Affiliated Hospital of Harbin Medical University, No. 23
Youzheng Road, Nangang District, Harbin 150081, Heilongjiang Province, P.R.
China. Tel: 86-451-85555721; Fax: 86-451-53643849;
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25
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Anani M, Nobuhisa I, Taga T. Sry-related High Mobility Group Box 17 Functions as a Tumor Suppressor by Antagonizing the Wingless-related Integration Site Pathway. J Cancer Prev 2020; 25:204-212. [PMID: 33409253 PMCID: PMC7783240 DOI: 10.15430/jcp.2020.25.4.204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/01/2020] [Accepted: 12/05/2020] [Indexed: 11/16/2022] Open
Abstract
A transcription factor Sry-related high mobility group box (Sox) 17 is involved in developmental processes including spermatogenesis, cardiovascular system, endoderm formation, and so on. In this article, we firstly review the studies on the relation between the Sox17 expression and tumor malignancy. Although Sox17 positively promotes various tissue development, most of the cancers associated with Sox17 show decreased expression levels of Sox17, and an inverse correlation between Sox17 expression and malignancy is revealed. We briefly discuss the mechanism of such Sox17 down-regulation by focusing on DNA methylation of CpG sites located in the Sox17 gene promoter. Next, we overview the function of Sox17 in the fetal hematopoiesis, particularly in the dorsal aorta in midgestation mouse embryos. The Sox17 expression in hematopoietic stem cell (HSC)-containing intra-aortic hematopoietic cell cluster (IAHCs) is important for the cluster formation with the hematopoietic ability. The sustained expression of Sox17 in adult bone marrow HSCs and the cells in IAHCs of the dorsal aorta indicate abnormalities that are low lymphocyte chimerism and the aberrant proliferation of common myeloid progenitors in transplantation experiments. We then summarize the perspectives of Sox17 research in cancer control.
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Affiliation(s)
- Maha Anani
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ikuo Nobuhisa
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuya Taga
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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26
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Ahn KS, Kang KJ. Molecular heterogeneity in intrahepatic cholangiocarcinoma. World J Hepatol 2020; 12:1148-1157. [PMID: 33442444 PMCID: PMC7772740 DOI: 10.4254/wjh.v12.i12.1148] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/01/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous primary liver cancer, and currently there exist only a few options of targeted therapy. Histopathologically, iCCA is sub-classified according to morphology (mass forming type, periductal infiltrating type, and intraductal growing type) and histology (small duct type and large duct type). According to different histopathological types, clinical features such as risk factors and prognosis vary. Recent developments in genomic profiling have revealed several molecular markers for poor prognosis and activation of oncogenic pathways. Exploration of molecular characteristics of iCCA in each patient is a major challenge in a clinical setting, and there is no effective molecular-based targeted therapy. However, several recent studies suggested molecular-based subtypes with corresponding clinical and pathological features. Even though the subtypes have not yet been validated, it is possible that molecular features can be predicted based on clinicopathological characteristics and that this could be used for a more rational approach to integrative clinical and molecular subclassification and targeted therapy. In this review, we explored the genomic landscape of iCCA and attempted to find relevance between clinicopathologic and molecular features in molecular subtypes in several published studies. The results reveal future directions that may lead to a rational approach to the targeted therapy.
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Affiliation(s)
- Keun Soo Ahn
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, South Korea.
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, South Korea
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27
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.,Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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28
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Tan DS, Holzner M, Weng M, Srivastava Y, Jauch R. SOX17 in cellular reprogramming and cancer. Semin Cancer Biol 2020; 67:65-73. [DOI: 10.1016/j.semcancer.2019.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 07/19/2019] [Accepted: 08/08/2019] [Indexed: 12/19/2022]
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29
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Personeni N, Lleo A, Pressiani T, Colapietro F, Openshaw MR, Stavraka C, Pouptsis A, Pinato DJ, Rimassa L. Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options. Cancers (Basel) 2020; 12:E3370. [PMID: 33202975 PMCID: PMC7696875 DOI: 10.3390/cancers12113370] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.
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Affiliation(s)
- Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Mark Robert Openshaw
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Chara Stavraka
- Department of Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK;
| | - Athanasios Pouptsis
- Department of Medical Oncology, “Euromedica” General Clinic, 54645 Thessaloniki, Greece;
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
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30
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Saleh M, Virarkar M, Bura V, Valenzuela R, Javadi S, Szklaruk J, Bhosale P. Intrahepatic cholangiocarcinoma: pathogenesis, current staging, and radiological findings. Abdom Radiol (NY) 2020; 45:3662-3680. [PMID: 32417933 DOI: 10.1007/s00261-020-02559-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To this date, it is a major oncological challenge to optimally diagnose, stage, and manage intrahepatic cholangiocarcinoma (ICC). Imaging can not only diagnose and stage ICC, but it can also guide management. Hence, imaging is indispensable in the management of ICC. In this article, we review the pathology, epidemiology, genetics, clinical presentation, staging, pathology, radiology, and treatment of ICC.
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Affiliation(s)
- Mohammed Saleh
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Mayur Virarkar
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vlad Bura
- Department of Radiology, County Clinical Emergency Hospital, 400006, Cluj-Napoca, Cluj, Romania
| | - Raul Valenzuela
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sanaz Javadi
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Janio Szklaruk
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Priya Bhosale
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
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31
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He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother 2020; 132:110851. [PMID: 33080466 DOI: 10.1016/j.biopha.2020.110851] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/27/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
The WNT/β-catenin signaling pathway is a highly conserved and tightly controlled molecular mechanism that regulates embryonic development, cellular proliferation and differentiation. Of note, accumulating evidence has shown that the aberrant of WNT/β-catenin signaling promotes the development and/or progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults. There are two different WNT signaling pathways have been identified, which were termed non-canonical and canonical pathways, the latter involving the activation of β-catenin. β-catenin, acting as an intracellular signal transducer in the WNT signaling pathway, is encoded by CTNNB1 and plays a critical role in tumorigenesis. In the past research, most liver tumors have mutations in genes encoding key components of the WNT/β-catenin signaling pathway. In addition, several of other signaling pathways also can crosswalk with β-catenin. In this review, we discuss the most relevant molecular mechanisms of action and regulation of WNT/β-catenin signaling in the development and pathophysiology of liver cancers, as well as in the development of therapeutics.
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Affiliation(s)
- Shuai He
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China
| | - Shilei Tang
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
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32
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1416] [Impact Index Per Article: 283.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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33
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Goeppert B. [Cholangiocarcinoma-diagnosis, classification, and molecular alterations]. DER PATHOLOGE 2020; 41:488-494. [PMID: 32757029 DOI: 10.1007/s00292-020-00808-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
BACKGROUND The entity cholangiocarcinoma comprises various malignant epithelial neoplasms of different morphology, etiology, and pathogenesis. AIM In this review, the etiology, pathogenesis, diagnostic criteria, classification, and molecular alterations of intra- and extrahepatic cholangiocarcinomas are summarized. MATERIAL AND METHODS This review is based on the currently available literature and personal knowledge. RESULTS AND DISCUSSION Cholangiocarcinomas are morphologically and molecularly diverse neoplasms that can develop ubiquitously in the biliary tract. Since there is a significant histological and immunohistochemical overlap with frequent liver metastases, a definite diagnosis can often only be rendered in the clinical context. Cholangiocarcinomas are subclassified into intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) tumors according to macro-anatomical criteria. Recent studies show that there are distinctive molecular differences in particular between iCCA and extrahepatic CCA (eCCA, including pCCA and dCCA). In addition, morphologically well-characterized precursor lesions have been identified, which in various frequencies can be assigned not only to the anatomical classification, but also to certain etiologies. An exact classification is therefore essential, especially with regard to the development of innovative, targeted therapeutic approaches.
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Affiliation(s)
- Benjamin Goeppert
- Pathologisches Institut, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Deutschland.
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Lozano E, Asensio M, Perez-Silva L, Banales JM, Briz O, Marin JJG. MRP3-Mediated Chemoresistance in Cholangiocarcinoma: Target for Chemosensitization Through Restoring SOX17 Expression. Hepatology 2020; 72:949-964. [PMID: 31863486 DOI: 10.1002/hep.31088] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 12/10/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS A limitation for the treatment of unresectable cholangiocarcinoma (CCA) is its poor response to chemotherapy, which is partly due to reduction of intracellular levels of anticancer drugs through ATP-binding cassette (ABC) pumps. Low expression of SOX17 (SRY-box containing gene 17), a transcription factor that promotes biliary differentiation and phenotype maintenance, has been associated with cholangiocyte malignant transformation. Whether SOX17 is also involved in CCA chemoresistance is investigated in this study. APPROACH AND RESULTS SOX17 expression in human CCA cells (EGI-1 and TFK-1) selectively potentiated cytotoxicity of SN-38, 5-fluorouracil and mitoxantrone, but not that of gemcitabine, capecitabine, cisplatin, or oxaliplatin. The analysis of the resistome by TaqMan low-density arrays revealed changes affecting primarily ABC pump expression. Single-gene quantitative real-time PCR, immunoblot, and immunofluorescence analyses confirmed that MRP3 (multidrug resistance associated protein 3), which was highly expressed in CCA human tumors, was down-regulated in SOX17-transduced CCA cells. The substrate specificity of this pump matched that of SOX17-induced in vitro selective chemosensitization. Functional studies showed lower ability of SOX17-expressing CCA cells to extrude specific MRP3 substrates. Reporter assay of MRP3 promoter (ABCC3pr) revealed that ABCC3pr activity was inhibited by SOX17 expression and SOX2/SOX9 silencing. The latter was highly expressed in CCA. Moreover, SOX2/9, but not SOX17, induced altered electrophoretic mobility of ABCC3pr, which was prevented by SOX17. The growth of CCA tumors subcutaneously implanted into immunodeficient mice was inhibited by 5-fluorouracil. This effect was enhanced by co-treatment with adenoviral vectors encoding SOX17. CONCLUSIONS SOX9/2/17 are involved in MRP3-mediated CCA chemoresistance. Restored SOX17 expression, in addition to its tumor suppression effect, induces selective chemosensitization due to MRP3 down-regulation and subsequent intracellular drug accumulation.
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Affiliation(s)
- Elisa Lozano
- Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos III National Health Institute, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, Salamanca, Spain
| | - Laura Perez-Silva
- Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, Salamanca, Spain
| | - Jesus M Banales
- National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos III National Health Institute, Madrid, Spain.,Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.,Ikerbasque, Bilbao, Spain
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos III National Health Institute, Madrid, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, Salamanca, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos III National Health Institute, Madrid, Spain
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35
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Emerging pathways for precision medicine in management of cholangiocarcinoma. Surg Oncol 2020; 35:47-55. [PMID: 32827952 DOI: 10.1016/j.suronc.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/06/2020] [Indexed: 12/27/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.
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Abstract
PURPOSE OF REVIEW Cholangiocarcinoma (CCA) are heterogeneous tumors that arise from the malignant transformation of cholangiocytes along the biliary tree. CCA heterogeneity occurs at multiple levels and results in resistance to therapy and poor prognosis. Here, we review the molecular classification of CCA by focusing on the latest progresses based on genetic, epigenetic, transcriptomic and proteomic profiles. In addition, we introduce the emerging field of radiogenomics. RECENT FINDINGS Genome-wide integrative omics approaches have been widely reported by using large cohorts of CCA patients. Morphomolecular correlations have been established, including enrichment of FGFR2 gene fusions and IDH1/2 mutations in iCCA. A specific IDH mutant iCCA subtype displays high mitochondrial and low chromatin modifier expression linked to ARID1A promoter hypermethylation. Examples of translation of these classifications for the management of CCA have also been reported, with prediction of drug efficacy based on genetic alterations. SUMMARY Although there is currently no international consensus on CCA morphomolecular classification, the recent initiatives developed under the umbrella of The European Network for the Study of Cholangiocarcinoma (ENSCCA) should favor new collaborative research. Identifying distinct molecular subgroups and developing appropriate targeted therapies will improve the clinical outcome of patients with CCA.
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37
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Wnt Signaling in the Regulation of Immune Cell and Cancer Therapeutics. Cells 2019; 8:cells8111380. [PMID: 31684152 PMCID: PMC6912555 DOI: 10.3390/cells8111380] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/21/2019] [Accepted: 11/01/2019] [Indexed: 12/17/2022] Open
Abstract
Wnt signaling is one of the important pathways to play a major role in various biological processes, such as embryonic stem-cell development, tissue regeneration, cell differentiation, and immune cell regulation. Recent studies suggest that Wnt signaling performs an essential function in immune cell modulation and counteracts various disorders. Nonetheless, the emerging role and mechanism of action of this signaling cascade in immune cell regulation, as well as its involvement in various cancers, remain debatable. The Wnt signaling in immune cells is very diverse, e.g., the tolerogenic role of dendritic cells, the development of natural killer cells, thymopoiesis of T cells, B-cell-driven initiation of T-cells, and macrophage actions in tissue repair, regeneration, and fibrosis. The purpose of this review is to highlight the current therapeutic targets in (and the prospects of) Wnt signaling, as well as the potential suitability of available modulators for the development of cancer immunotherapies. Although there are several Wnt inhibitors relevant to cancer, it would be worthwhile to extend this approach to immune cells.
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38
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Intuyod K, Armartmuntree N, Jusakul A, Sakonsinsiri C, Thanan R, Pinlaor S. Current omics-based biomarkers for cholangiocarcinoma. Expert Rev Mol Diagn 2019; 19:997-1005. [PMID: 31566016 DOI: 10.1080/14737159.2019.1673162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke (Opisthorchis viverrini) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered: In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion: Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories.
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Affiliation(s)
- Kitti Intuyod
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Napat Armartmuntree
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University , Khon Kaen , Thailand
| | - Chadamas Sakonsinsiri
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Raynoo Thanan
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
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39
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Higashijima Y, Kanki Y. Molecular mechanistic insights: The emerging role of SOXF transcription factors in tumorigenesis and development. Semin Cancer Biol 2019; 67:39-48. [PMID: 31536760 DOI: 10.1016/j.semcancer.2019.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/31/2019] [Accepted: 09/15/2019] [Indexed: 01/22/2023]
Abstract
Over the last decade, the development and progress of next-generation sequencers incorporated with classical biochemical analyses have drastically produced novel insights into transcription factors, including Sry-like high-mobility group box (SOX) factors. In addition to their primary functions in binding to and activating specific downstream genes, transcription factors also participate in the dedifferentiation or direct reprogramming of somatic cells to undifferentiated cells or specific lineage cells. Since the discovery of SOX factors, members of the SOXF (SOX7, SOX17, and SOX18) family have been identified to play broad roles, especially with regard to cardiovascular development. More recently, SOXF factors have been recognized as crucial players in determining the cell fate and in the regulation of cancer cells. Here, we provide an overview of research on the mechanism by which SOXF factors regulate development and cancer, and discuss their potential as new targets for cancer drugs while offering insight into novel mechanistic transcriptional regulation during cell lineage commitment.
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Affiliation(s)
- Yoshiki Higashijima
- Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan
| | - Yasuharu Kanki
- Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
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40
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Chen G, Chen H, Ren S, Xia M, Zhu J, Liu Y, Zhang L, Tang L, Sun L, Liu H, Dong Z. Aberrant DNA methylation of mTOR pathway genes promotes inflammatory activation of immune cells in diabetic kidney disease. Kidney Int 2019; 96:409-420. [DOI: 10.1016/j.kint.2019.02.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 02/19/2019] [Accepted: 02/21/2019] [Indexed: 01/19/2023]
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41
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Wang W, Smits R, Hao H, He C. Wnt/β-Catenin Signaling in Liver Cancers. Cancers (Basel) 2019; 11:E926. [PMID: 31269694 PMCID: PMC6679127 DOI: 10.3390/cancers11070926] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/24/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.
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Affiliation(s)
- Wenhui Wang
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam 3015 CN, The Netherlands
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
| | - Chaoyong He
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
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42
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O'Rourke CJ, Lafuente-Barquero J, Andersen JB. Epigenome Remodeling in Cholangiocarcinoma. Trends Cancer 2019; 5:335-350. [PMID: 31208696 DOI: 10.1016/j.trecan.2019.05.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma (CCA) comprises a heterogeneous collection of malignancies arising within the biliary tract, characterized by late diagnosis, innate chemoresistance, and abysmal prognosis. Sequencing data have uncovered recurrent mutations in diverse epigenetic regulators, implicating epigenetic destabilization at the root of these tumors. However, few studies have characterized biliary tumor epigenomes. In this Opinion article, we argue that an epigenome-oriented approach to CCA could establish diverse interconnections between many key aspects of research on this disease, including molecular heterogeneity, diverse cells of origin, and prominent tumor microenvironments. Moreover, we discuss plausible causes of epigenome dysregulation in biliary tumors, including genetic, epigenetic, metabolic, microenvironmental, and physiological factors. Lastly, we assess the translational potential of epigenomics in CCA to uncover robust biomarkers and therapeutic opportunities for this growing group of patients with limited treatment options.
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Affiliation(s)
- Colm J O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Juan Lafuente-Barquero
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
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43
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Braconi C, Roessler S, Kruk B, Lammert F, Krawczyk M, Andersen JB. Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine? Liver Int 2019; 39 Suppl 1:32-42. [PMID: 30829432 DOI: 10.1111/liv.14085] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 12/11/2022]
Abstract
The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlie the diversity of growth patterns of this malignancy remain a clinical concern. Tumours of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome-wide tumour heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behaviour. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies.
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Affiliation(s)
- Chiara Braconi
- Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.,Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Trust, Surrey and London, UK
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Beata Kruk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.,Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark
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44
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Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, Carpino G. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:7-18. [PMID: 30882996 DOI: 10.1111/liv.14093] [Citation(s) in RCA: 225] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin-producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub-classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho-molecular groups can currently be discriminated. Large-duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2-fusions are typically seen in small-duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.
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Affiliation(s)
- Timothy Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
| | - Joanne Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria Guido
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Benjamin Goeppert
- Department of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
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45
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Ghosh N, Hossain U, Mandal A, Sil PC. The Wnt signaling pathway: a potential therapeutic target against cancer. Ann N Y Acad Sci 2019; 1443:54-74. [PMID: 31017675 DOI: 10.1111/nyas.14027] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/05/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
The role of the evolutionarily conserved Wnt signaling pathway is well documented in several cellular processes, such as cell proliferation, differentiation, cell motility, and maintenance of the stem cell niche. The very first indication that aberrant Wnt signaling can cause carcinogenesis came from a finding that the mutation of the adenomatous polyposis coli gene (APC) predisposes a person to colorectal carcinoma. Later, with progressing research it became clear that abnormal activation or mutation of the genes related to this pathway could drive tumorigenesis. Here, we review recent advances in research regarding Wnt signaling regulation and its role in several cancer subtypes. Additionally, the utility of Wnt pathway-targeted cancer therapy intervention is also highlighted, with an overview of current approaches to target the Wnt pathway in oncogenesis and the future scopes and challenges associated with them.
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Affiliation(s)
- Noyel Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Uday Hossain
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Ankita Mandal
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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46
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Goeppert B. [Biliary tract cancers : Molecular characterization and identification of novel prognostic markers]. DER PATHOLOGE 2019; 38:192-197. [PMID: 29063951 DOI: 10.1007/s00292-017-0359-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Bile duct cancers (BTCs) are highly aggressive tumors with a dismal prognosis and an increasing incidence. BTC is a tumorbiologically and clinically heterogeneous tumor group and can be subdivided according to anatomical aspects into intrahepatic cholangiocarcinomas (iCCA), extrahepatic cholangiocarcinomas (eCCA) and gallbladder carcinomas (GBC). NEW THERAPY OPTIONS Chronic inflammatory processes of the biliary system seem to play a role in the development of these tumors. Insights into molecular cholangiocarcinogenesis could make an important contribution to novel and more precise classification attempts and to the development of new, targeted therapies for BTC. EPIGENETIC AND GENETIC ALTERATIONS IN CHOLANGIOCARCINOMAS The first description of genome-wide DNA methylation patterns in CCA showed drastic global methylation differences between CCA and corresponding non-neoplastic tissue (matched-pair analyses). Moreover, significant methylation differences between the CCA subtypes (eCCA and iCCA) could be found. Using immunohistochemistry and Sanger sequencing, it was shown that the actual BRAF V600E mutation rate seems to be significantly lower (1.3%) than previously described in the literature. IMMUNEPHENOTYPING IN BILIARY TRACT CANCERS A comprehensive, subtype-specific characterization of tumor-infiltrating immune cells as well as an expression analysis of Major Histocompatibility Complex I was performed in a large and well-characterized BTC cohort. For further studies on the efficacy of immunomodulatory therapy approaches for BTC, the presented results provide a solid basis.
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Affiliation(s)
- B Goeppert
- Pathologisches Institut, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Deutschland.
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47
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Goeppert B, Truckenmueller F, Ori A, Fritz V, Albrecht T, Fraas A, Scherer D, Silos RG, Sticht C, Gretz N, Mehrabi A, Bewerunge-Hudler M, Pusch S, Bermejo JL, Dietrich P, Schirmacher P, Renner M, Roessler S. Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p. Sci Rep 2019; 9:4796. [PMID: 30886199 PMCID: PMC6423323 DOI: 10.1038/s41598-019-40857-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 02/25/2019] [Indexed: 12/13/2022] Open
Abstract
Gallbladder carcinoma (GBC) is a biliary tract cancer with few treatment options and poor prognosis. Radical surgery is the only potentially curative treatment option but most patients diagnosed with GBC are unresectable. Thus, there is a great need for the development of new treatment options including targeted therapy. Here, we aimed at identifying deregulated miRNAs and affected pathways involved in GBC development and progression. We performed global miRNA profiling of 40 GBC and 8 normal gallbladder tissues and identified large differences with 30% of miRNAs being differentially expressed (false discovery rate: FDR < 0.001). We found 24 miRNAs to be differentially regulated in GBC with poor outcome (p < 0.05) of which miR-145-5p was the most downregulated miRNA. Overexpression of miR-145-5p significantly reduced cell proliferation and colony formation. Gene expression analysis of cells expressing miR-145-5p mimics revealed activation of the Signal transducer and activator of transcription 1 (STAT1) signaling pathway which is mainly tumor suppressive. Furthermore, the activation of STAT1 by miR-145-5p was specifically observed in gallbladder carcinoma and cholangiocarcinoma but not in hepatocellular carcinoma cells. The Protein Tyrosine Phosphatase Receptor Type F (PTPRF) is downregulated upon miR-145 expression and may be involved in STAT1 regulation. In addition, we found that the STAT1-regulated protein IRF7 is downregulated in GBC compared to normal gallbladder tissue and low IRF7 expression is associated with significantly lower overall survival of GBC patients. Thus, this study identified GBC patient subgroups and provides new mechanistic insights in the tumor suppressive function of miR-145-5p leading to activation of STAT1 signaling.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Alessandro Ori
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Valerie Fritz
- Institute of Biochemistry, Emil-Fischer Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Albrecht
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Angelika Fraas
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Rosa González Silos
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Carsten Sticht
- Center of Medical Research, University Hospital Mannheim, Mannheim, Germany
| | - Norbert Gretz
- Center of Medical Research, University Hospital Mannheim, Mannheim, Germany
| | - Arianeb Mehrabi
- Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Melanie Bewerunge-Hudler
- Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan Pusch
- Heidelberg University Hospital, Institute of Pathology, Department of Neuropathology, Heidelberg, Germany and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Emil-Fischer Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
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Abstract
The canonical Wnt-β-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt-β-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt-β-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt-β-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt-β-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt-β-catenin activation, mostly as a result of β-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt-β-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research.
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Kleinegger F, Hofer E, Wodlej C, Golob-Schwarzl N, Birkl-Toeglhofer AM, Stallinger A, Petzold J, Orlova A, Krassnig S, Reihs R, Niedrist T, Mangge H, Park YN, Thalhammer M, Aigelsreiter A, Lax S, Garbers C, Fickert P, Rose-John S, Moriggl R, Rinner B, Haybaeck J. Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival. Biochim Biophys Acta Mol Basis Dis 2019; 1865:308-321. [DOI: 10.1016/j.bbadis.2018.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/25/2018] [Accepted: 11/07/2018] [Indexed: 02/08/2023]
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50
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Kim Y, Lee K, Jeong S, Wen X, Cho NY, Kang GH. DLEC1 methylation is associated with a better clinical outcome in patients with intrahepatic cholangiocarcinoma of the small duct subtype. Virchows Arch 2019; 475:49-58. [DOI: 10.1007/s00428-018-02511-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/07/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022]
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