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Biliary tract cancer stem cells-translational options and challenges

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World Journal of Gastroenterology 2017年第14期23卷 2470-2482页

作者： Christian Mayr Matthias Ocker Markus Ritter Martin Pichler daniel neureiter Tobias Kiesslich Department of Internal Medicine I Paracelsus Medical University Laboratory for Tumour Biology and Experimental Therapies Institute of Physiology and PathophysiologyParacelsus Medical University Tanslational Medicine Oncology Department of Gastroenterology CBF CharitéUniversity Medicine Berlin Laboratory for Tumour Biology and Experimental Therapies(TREAT) Laboratory for Functional and Molecular Membrane PhysiologyParacelsus Medical University Department for Radon Therapy Research Ludwig Boltzmann Cluster for Arthritis and RehabilitationInstitute of Physiology and PathophysiologyParacelsus Medical University Research Unit for Non-coding RNA and genome editing in cancer Division of OncologyDepartment of Internal MedicineMedical University of Graz Institute of Pathology Paracelsus Medical University Cancer Cluster Salzburg

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

关键词： Biliary tract cancer cancer stem cells Cancer stem cell markers Tumor microenvironment Micro-RNAs

Role of the receptor for advanced glycation end products in hepatic fibrosis

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World Journal of Gastroenterology 2009年第46期15卷 5789-5798页

作者： Christina Lohwasser daniel neureiter Yury Popov Michael Bauer Detlef Schuppan Department of Medicine Ⅰ University of Erlangen-NurembergErlangen-Nürnberg Institute of Pathology Paracelsus Private Medicine UniversitySalzburg Division of Gastroenterology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBoston

AIM:To study the role of advanced glycation end products(AGE)and their specifi c receptor(RAGE)in the pathogenesis of liver fi brogenesis.METHODS:In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells(HSC)were measured after stimulation with the two RAGE ligands,advanced glycation end product-bovine serum albumin(AGE-BSA)and Nε-(carboxymethyl)lysine(CML)-BSA,or with tumor necrosis factor-α(TNF-α).In vivo RAGE expression was examined in models of hepatic fi brosis induced by bile duct ligation or thioacetamide.The effects of AGE-BSA and CML-BSA on HSC proliferation,signal transduction and profi brogenic gene expression were studied in vitro.RESULTS:In hepatic fibrosis,RAGE expression was enhanced in activated HSC,and also in endothelial cells,inflammatory cells and activated bile duct epithelia.HSC expressed RAGE which was upregulated after stimulation with AGE-BSA,CML-BSA,and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation,apoptosis,fibrogenic signal transduction and fibrosis-or fibrolysis-related gene expression,except for marginal upregulation of procollagen α1(Ⅰ)mRNA by AGE-BSA.CONCLUSION:Despite upregulation of RAGE in activated HSC,RAGE stimulation by AGE does not alter their fibrogenic activation.Therefore,RAGE does not contribute directly to hepatic fibrogenesis.

关键词：糖基化终产物肝纤维化最终产品受体牛血清白蛋白肿瘤坏死因子-α 细胞外基质晚期

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

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World Journal of Gastroenterology 2014年第24期20卷 7830-7848页

作者： daniel neureiter Tarkan Jger Matthias Ocker Tobias Kiesslich Institute of Pathology Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Department of Surgery Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Experimental Medicine Oncology Bayer Pharma AG13342 BerlinGermany Department of Internal Medicine I Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Institute of Physiology and Pathophysiology Paracelsus Medical University5020 SalzburgAustria

An improvement in pancreatic cancer treatment represents an urgent medical goal.Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades.Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations,such as mutations of K-ras,and especially epigenetic dysregulation of tumor-associated genes,such as silencing of the tumor suppressor p16ink4a,are hallmarks of pancreatic cancer.Here,we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation,histone acetylation or miRNA(microRNA)expression,and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition,morphological pattern formation,or cancer stem cell regulation during carcinogenesis from PanIN(pancreatic intraepithelial lesions)to invasive cancer and resistance development.Epigenetic drugs,such as DNA methyltransferases or histone deactylase inhibitors,have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development.Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.

关键词： Pancreatic cancer Epigenetics DNA methylation Hist

Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

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World Journal of Gastrointestinal Oncology 2015年第12期7卷 473-483页

作者： Eckhard Klieser Stefan Swierczynski Christian Mayr Johanna Schmidt daniel neureiter Tobias Kiesslich Romana Illig Institute of Pathology Paracelsus Medical UniversitySalzburger Landeskliniken (SALK) 5020 Salzburg Austria Department of Surgery Paracelsus Medical University Salzburger Landeskliniken (SALK) 5020 SalzburgAustria Department of Internal Medicine I Paracelsus Medical University Salzburger Landes- kliniken (SALK) 5020 Salzburg Austria Laboratory for Tumour Biology and Experimental Therapies (TREAT) Institute of Physiology and Pathophysiology Paracelsus Medical University

In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis(AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future thera-pies. Histone deacetylases(HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcri-ption. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.

关键词： Pancreatitis Pancreatic cancer Epigenetics Histone

Differential role of Hedgehog signaling in human pancreatic(patho-)physiology:An up to date review

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World Journal of Gastrointestinal Pathophysiology 2016年第2期7卷 199-210页

作者： Eckhard Klieser Stefan Swierczynski Christian Mayr Tarkan Jager Johanna Schmidt daniel neureiter Tobias Kiesslich Romana Illig Institute of Pathology Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Department of Surgery Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Department of Internal Medicine I Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Laboratory for Tumour Biology and Experimental Therapies(TREAT) Institute of Physiology and PathophysiologyParacelsus Medical University

Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last decades.This is the case especially concerning the pancreas,however,real therapeutic breakthroughs are missing until now.In general,Hh signaling is essential for pancreatic organogenesis,development,and tissue maturation.In the case of acute pancreatitis,Hh has a protective role,whereas in chronic pancreatitis,Hh interacts with pancreatic stellate cells,leading to destructive parenchym fibrosis and atrophy,as well as to irregular tissue remodeling with potency of initiating cancerogenesis.In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment.The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials(phases 1 and 2).Furthermore,a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach.In this review,we give a structured survey of the role of the Hh pathway in pancreatic development,pancreatitis,pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

关键词： Pancreatic cancer Hedgehog Pancreatitis Pancreas Development

Intrathoracic major duodenal papilla with transhiatal herniation of the pancreas and duodenum:A case report and review of the literature

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World Journal of Gastrointestinal Surgery 2013年第6期5卷 202-206页

作者： Tarkan Jger daniel neureiter Clemens Nawara Adam Dinnewitzer Dietmar fner Wolfram Lamadé Department of Surgery Paracelsus Medical University5020 SalzburgAustria Institute of Pathology Paracelsus Medical University/Salzburger Landeskliniken5020 SalzburgAustria Department of Surgery Helios Spital88662 überlingenGermany

Transhiatal herniation of the pancreas is an extremely rare condition.In the published literature we found only eleven cases reported in the period of 1958 to 2011.A coincidental hiatal herniation of the duodenum is described in two cases only.To our knowledge,we report the first case with a hiatal herniation of the complete duodenum and proximal pancreas presenting an intrathoracic major duodenal papilla with consecutive intrahepatic and extrahepatic cholestasis.A 72-yearold Caucasian woman was admitted to our department with a hiatal hernia grade Ⅳ for further evaluation.According to our recommendation of surgical hernia repair soon after the diagnosis of a transhiatal herniation of the proximal pancreas and entire duodenum,we had to respect the declared intention of the patient for a conservative procedure.So we were forced to wait for surgical repair within an emergency situation complicated by a myocardial infarction and reduced general condition.We discuss the therapeutic decision making process and a complete literature review of this rare entity.

关键词： Hiatal hernia Paraesophageal hernia Intrathoracic pancreas Intrathoracic duodenum Diaphragmatic hernia