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Pancreatic Neoplasms: HELP
Articles by Alexander Arlt
Based on 17 articles published since 2010
(Why 17 articles?)
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Between 2010 and 2020, A. Arlt wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial Investigational histone deacetylase inhibitors for treating pancreatic adenocarcinoma. 2016

Arlt, Alexander / Schäfer, Heiner. ·a Department of Internal Medicine I , Laboratory for Gastrointestinal Signal Transduction, UKSH Campus Kiel , Kiel , Germany. · b Institute for Experimental Cancer Research , Laboratory of Molecular Gastroenterology, - Christian-Albrechts-University & UKSH Campus Kiel , Kiel , Germany. ·Expert Opin Investig Drugs · Pubmed #27666721.

ABSTRACT: -- No abstract --

2 Review NF-κB Dependent Chemokine Signaling in Pancreatic Cancer. 2019

Geismann, Claudia / Schäfer, Heiner / Gundlach, Jan-Paul / Hauser, Charlotte / Egberts, Jan-Hendrik / Schneider, Günter / Arlt, Alexander. ·Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. cgeismann@email.uni-kiel.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. hschaef@1med.uni-kiel.de. · Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany. hschaef@1med.uni-kiel.de. · Department of Surgery, UKSH-Campus Kiel, 24105 Kiel, Germany. jan-paul.gundlach@uksh.de. · Department of Surgery, UKSH-Campus Kiel, 24105 Kiel, Germany. charlotte.hauser@uksh.de. · Department of Surgery, UKSH-Campus Kiel, 24105 Kiel, Germany. jan-hendrik.egberts@uksh.de. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany. guenter.schneider@tum.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. alexander.arlt@uksh.de. ·Cancers (Basel) · Pubmed #31561620.

ABSTRACT: Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.

3 Review Targeting apoptosis pathways in pancreatic cancer. 2013

Arlt, Alexander / Müerköster, Susanne Sebens / Schäfer, Heiner. ·Laboratory of Molecular Gastroenterology and Hepatology, Dept. of Internal Medicine 1, UKSH-Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany. ·Cancer Lett · Pubmed #21078544.

ABSTRACT: Pancreatic cancer - here in particular pancreatic ductal adenocarcinoma (PDAC) - is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials - either in neoadjuvant/adjuvant or in palliative treatments.

4 Article The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2. 2019

Kha, My-Lan / Hesse, Lisa / Deisinger, Florian / Sipos, Bence / Röcken, Christoph / Arlt, Alexander / Sebens, Susanne / Helm, Ole / Schäfer, Heiner. ·Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany. · Institute of Pathology, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 14, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Laboratory of Gastrointestinal Signal Transduction, Department of Internal Medicine I, UKSH Campus Kiel, Bldg. 6, Arnold-Heller-Straße 3, 24105 Kiel, Germany. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. hschaef@1med.uni-kiel.de. ·Oncogene · Pubmed #30302023.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.

5 Article TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines. 2018

Geismann, Claudia / Erhart, Wiebke / Grohmann, Frauke / Schreiber, Stefan / Schneider, Günter / Schäfer, Heiner / Arlt, Alexander. ·Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. cgeismann@email.uni-kiel.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. wiebke.erhart@uksh.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. fraukethun@gmx.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. s.schreiber@mucosa.de. · Institute of Clinical Molecular Biology, UKSH Campus Kiel, 24105 Kiel, Germany. s.schreiber@mucosa.de. · Technische Universität München, Klinikum Rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany. guenter.schneider@tum.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. hschaef@1med.uni-kiel.de. · Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany. hschaef@1med.uni-kiel.de. · Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany. aarlt@1med.uni-kiel.de. ·Int J Mol Sci · Pubmed #29867042.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance.

6 Article MTOR inhibitor-based combination therapies for pancreatic cancer. 2018

Hassan, Zonera / Schneeweis, Christian / Wirth, Matthias / Veltkamp, Christian / Dantes, Zahra / Feuerecker, Benedikt / Ceyhan, Güralp O / Knauer, Shirley K / Weichert, Wilko / Schmid, Roland M / Stauber, Roland / Arlt, Alexander / Krämer, Oliver H / Rad, Roland / Reichert, Maximilian / Saur, Dieter / Schneider, Günter. ·Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany. · Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany. · Institute of Pathology, Technische Universität München, 81675 München, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany. · Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Br J Cancer · Pubmed #29384525.

ABSTRACT: BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

7 Article Management of patients with pancreatic cystic lesions: A case-based survey. 2017

Müssle, B / Distler, M / Wolk, S / Shrikhande, S V / Aust, D E / Arlt, A / Weitz, J / Hackert, T / Welsch, T. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai, 400012, India. · Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Department of Internal Medicine I, Christian-Albrechts-University & UKSH Campus Kiel, Kiel, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de. ·Pancreatology · Pubmed #28456590.

ABSTRACT: BACKGROUND: Pancreatic cystic lesions (PCL), including intraductal papillary mucinous neoplasia (IPMN), harbor different malignant potential and the optimal management is often challenging. The present study aims to depict the compliance of experts with current consensus guidelines and the accuracy of treatment recommendations stratified by the medical specialty and hospital volume. METHODS: An international survey was conducted using a set of 10 selected cases of PCL that were presented to a cohort of international experts on pancreatology. All presented cases were surgically resected between 2004 and 2015 and histopathological examination was available. Accuracy of the treatment recommendations was based on the European and international consensus guideline algorithms, and the histopathological result. RESULTS: The response rate of the survey was 26% (46 of 177 contacted experts), consisting of 70% surgeons and 30% gastroenterologists/oncologists (GI/Onc). In the case of main-duct IPMN (MD-IPMN), surgeons preferred more often the surgical approach in comparison with the GI/Onc (55 versus 44%). The mean accuracy rate based on the European and international consensus guidelines, and the histopathological result, were 71/76/38% (surgeons), and 70/73/34% (GI/Onc), respectively. High-volume centers achieved insignificantly higher accuracy scores with regard to the histopathology. Small branch-duct IPMN with cysts <2 cm and malignant potential were not identified by the guideline algorithms. CONCLUSION: The survey underlines the complexity of treatment decisions for patients with PCL; less than 40% of the recommendations were in line with the final histopathology in this selected case panel. Experts and consensus guidelines may fail to predict malignant potential in small PCL.

8 Article Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer. 2017

Geismann, Claudia / Grohmann, Frauke / Dreher, Anita / Häsler, Robert / Rosenstiel, Philip / Legler, Karen / Hauser, Charlotte / Egberts, Jan Hendrik / Sipos, Bence / Schreiber, Stefan / Linkermann, Andreas / Hassan, Zonera / Schneider, Günter / Schäfer, Heiner / Arlt, Alexander. ·Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany. · Department of Surgery, UKSH Campus Kiel, Kiel, German. · Institute of Pathology, University Hospital Tübingen, Tübingen, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Experimental Cancer Research, UKSH Campus Kiel, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. Electronic address: aarlt@1med.uni-kiel.de. ·Biochim Biophys Acta Mol Cell Res · Pubmed #28188806.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.

9 Article HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. 2017

Stojanovic, N / Hassan, Z / Wirth, M / Wenzel, P / Beyer, M / Schäfer, C / Brand, P / Kroemer, A / Stauber, R H / Schmid, R M / Arlt, A / Sellmer, A / Mahboobi, S / Rad, R / Reichert, M / Saur, D / Krämer, O H / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz, Germany. · Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ·Oncogene · Pubmed #27721407.

ABSTRACT: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

10 Article Endoscopic ultrasound-guided biliary drainage using a lumen-apposing self-expanding metal stent: a case series. 2015

Brückner, Stefan / Arlt, Alexander / Hampe, Jochen. ·Medical Department 1, University Hospital Dresden, Technical University Dresden (TUD), Dresden, Germany. · Department of Medicine I, University Hospital Schleswig-Holstein, Kiel Campus, Christian-Albrechts-University Kiel, Kiel, Germany. ·Endoscopy · Pubmed #26021309.

ABSTRACT: Endoscopic ultrasound-guided biliary drainage (EUS-BD) might be an alternative to percutaneous or transpapillary biliary drainage in unresectable pancreatic or biliary cancer. A lumen-apposing, fully covered, self-expanding metal stent, which creates a sealed transluminal conduit between the biliary and gastrointestinal tract may offer advantages over conventional plastic and metal stents. In this retrospective, observational, open-label case study, five patients underwent EUS-BD for obstructive jaundice in pancreatic cancer (n = 4) or distal cholangiocarcinoma (n = 1). Technical and functional success was achieved in all patients without complications. The development of specialized stent and delivery systems may render EUS-BD an effective and safe alternative to percutaneous or transpapillary approaches.

11 Article c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells. 2014

Geismann, C / Grohmann, F / Sebens, S / Wirths, G / Dreher, A / Häsler, R / Rosenstiel, P / Hauser, C / Egberts, J-H / Trauzold, A / Schneider, G / Sipos, B / Zeissig, S / Schreiber, S / Schäfer, H / Arlt, A. ·Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute for Experimental Medicine, Kiel, Germany. · Institute of Clinical Molecular Biology, Kiel, Germany. · Department of Surgery, Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, Kiel, Germany. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany. · Institute of Pathology, University Hospital Tübingen, Tübingen, Germany. · 1] Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany [2] Institute of Clinical Molecular Biology, Kiel, Germany. ·Cell Death Dis · Pubmed #25299780.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-κB signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-κB activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-κB-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-κB complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.

12 Article [Diagnosis and differential diagnosis of panceatic lesions]. 2013

Arlt, A / Ellrichmann, M / Schreiber, S / Mönig, H. ·Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel. ·Dtsch Med Wochenschr · Pubmed #24281965.

ABSTRACT: -- No abstract --

13 Article Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. 2013

Arlt, A / Sebens, S / Krebs, S / Geismann, C / Grossmann, M / Kruse, M-L / Schreiber, S / Schäfer, H. ·Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH, Kiel, Germany. ·Oncogene · Pubmed #23108405.

ABSTRACT: Evidence accumulates that the transcription factor nuclear factor E2-related factor 2 (Nrf2) has an essential role in cancer development and chemoresistance, thus pointing to its potential as an anticancer target and undermining its suitability in chemoprevention. Through the induction of cytoprotective and proteasomal genes, Nrf2 confers apoptosis protection in tumor cells, and inhibiting Nrf2 would therefore be an efficient strategy in anticancer therapy. In the present study, pancreatic carcinoma cell lines (Panc1, Colo357 and MiaPaca2) and H6c7 pancreatic duct cells were analyzed for the Nrf2-inhibitory effect of the coffee alkaloid trigonelline (trig), as well as for its impact on Nrf2-dependent proteasome activity and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and anticancer drug-induced apoptosis. Chemoresistant Panc1 and Colo357 cells exhibit high constitutive Nrf2 activity, whereas chemosensitive MiaPaca2 and H6c7 cells display little basal but strong tert-butylhydroquinone (tBHQ)-inducible Nrf2 activity and drug resistance. Trig efficiently decreased basal and tBHQ-induced Nrf2 activity in all cell lines, an effect relying on a reduced nuclear accumulation of the Nrf2 protein. Along with Nrf2 inhibition, trig blocked the Nrf2-dependent expression of proteasomal genes (for example, s5a/psmd4 and α5/psma5) and reduced proteasome activity in all cell lines tested. These blocking effects were absent after treatment with Nrf2 siRNA, a condition in which proteasomal gene expression and proteasome activity were already decreased, whereas siRNA against the related transcription factor Nrf1 did not affect proteasome activity and the inhibitory effect of trig. Depending on both Nrf2 and proteasomal gene expression, the sensitivity of all cell lines to anticancer drugs and TRAIL-induced apoptosis was enhanced by trig. Moreover, greater antitumor responses toward anticancer drug treatment were observed in tumor-bearing mice when receiving trig. In conclusion, representing an efficient Nrf2 inhibitor capable of blocking Nrf2-dependent proteasome activity and thereby apoptosis protection in pancreatic cancer cells, trig might be beneficial in improving anticancer therapy.

14 Article Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells. 2011

Kürbitz, Claudia / Heise, Daniel / Redmer, Torben / Goumas, Freya / Arlt, Alexander / Lemke, Johannes / Rimbach, Gerald / Kalthoff, Holger / Trauzold, Anna. ·Division of Molecular Oncology, Institute of Experimental Cancer Research, CCC North, Kiel, Germany. ·Cancer Sci · Pubmed #21241417.

ABSTRACT: Green tea catechins are considered as possible cancer preventive agents for several cancer types but little is known regarding their effects on pancreatic cancer cells. The best studied catechin and the major polyphenol present in green tea is epigallocatechin gallate (EGCG). In the present study, we investigated the in vitro anti-tumoral properties of EGCG on human pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in comparison with the effects of two minor components of green tea catechins, catechin gallate (CG) and epicatechin gallate (ECG). We found that all three catechins inhibited proliferation of PDAC cells in a dose- and time-dependent manner. Interestingly, CG and ECG exerted much stronger anti-proliferative effects than EGCG. Western blot analyses performed with PancTu-I cells revealed catechin-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases [CDK], CDK inhibitors). Again, these effects were clearly more pronounced in CG or ECG than in EGCG-treated cells. Importantly, catechins, in particular ECG, inhibited TNFα-induced activation of NF-κB and consequently secretion of pro-inflammatory and invasion promoting proteins like IL-8 and uPA. Overall, our data show that green tea catechins ECG and CG exhibit potent and much stronger anti-proliferative and anti-inflammatory activities on PDAC cells than the most studied catechin EGCG.

15 Article Binding of the transcription factor Slug to the L1CAM promoter is essential for transforming growth factor-β1 (TGF-β)-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. 2011

Geismann, Claudia / Arlt, Alexander / Bauer, Iris / Pfeifer, Marco / Schirmer, Uwe / Altevogt, Peter / Müerköster, Susanne Sebens / Schäfer, Heiner. ·Department of Internal Medicine 1, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Arnold-Heller-Strasse 3, Bldg. 6, 24105 Kiel, Germany. ·Int J Oncol · Pubmed #21109948.

ABSTRACT: Members of the Slug/Snail family of transcription factors are thought to drive epithelial-mesenchymal-transition (EMT) in preneoplastic epithelial cells, thereby contributing to malignant transformation. One mediator in the EMT of pancreatic ductal adenocarcinoma (PDAC) cells and a potential target gene of Slug is the cellular adhesion molecule L1CAM. Using the human pancreatic ductal epithelial cell line H6c7 and the PDAC cell line Panc1, we could show that along with TGF-β1-induced EMT, L1CAM expression is increased in a Slug- but not Snail-dependent fashion. Two E-box recognition motifs in the L1CAM promoter upstream of the most distal transcriptional start site could be verified by gel shift and supershift assay to interact with Slug. ChIP assays detected an increased interaction of Slug with both recognition motifs of the human L1CAM promoter in TGF-β1-treated H6c7 cells, whereas binding of Snail was downregulated. Moreover, ChIP assays with Panc1 cells confirmed this interaction of Slug with the human L1CAM promoter and further detected an interaction of both recognition sites with RNA-polymerase II in a Slug-dependent fashion. Luciferase reporter gene assays using wild-type or single- and double-mutated variants of the L1CAM promoter confirmed transcriptional activation by Slug involving both recognition motifs. By demonstrating the direct transcriptional control of L1CAM expression through Slug during TGF-β1-induced EMT of PDAC cells, our findings point to a novel mechanism by which Slug contributes quite early to tumorigenesis. Moreover, our study is the first one describing the control of the human L1CAM promoter in tumor cells.

16 Article L1CAM-integrin interaction induces constitutive NF-kappaB activation in pancreatic adenocarcinoma cells by enhancing IL-1beta expression. 2010

Kiefel, H / Bondong, S / Erbe-Hoffmann, N / Hazin, J / Riedle, S / Wolf, J / Pfeifer, M / Arlt, A / Schäfer, H / Müerköster, S Sebens / Altevogt, P. ·Translational Immunology, German Cancer Research Center, Heidelberg, Germany. ·Oncogene · Pubmed #20543863.

ABSTRACT: L1 cell adhesion molecule (L1CAM) overexpression is often associated with bad prognosis in various human carcinomas. Recent studies also suggest a role of L1CAM in pancreatic ductal adenocarcinomas (PDAC). To further address its contribution, we expressed functional domains of L1CAM in PT45-P1 PDAC cells. We found that L1CAM that is full length (L1-FL), but neither the soluble ectodomain (L1ecto) nor the cytoplasmic part (L1cyt), could enhance cell proliferation or tumour growth in mice. Expression of L1-FL resulted in constitutive activation of NF-kappaB, which was abolished by L1CAM knockdown. We showed that the expression of IL-1beta was selectively upregulated by L1-FL, and increased IL-1beta levels were instrumental for sustained NF-kappaB activation. IL-1beta production and NF-kappaB activation were abolished by knockdown of alpha5-integrin and integrin-linked kinase, but insensitive to depletion of L1CAM cleavage proteinases. Supporting these data, PT45-P1 cells transduced with an L1CAM mutant deficient in integrin binding (L1-RGE) did not support the described L1-FL functions. Our results suggest that membranous L1CAM interacts with RGD-binding integrins, leading to sustained NF-kappaB activation by IL-1beta production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells.

17 Article HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells. 2010

Schüler, Susanne / Fritsche, Petra / Diersch, Sandra / Arlt, Alexander / Schmid, Roland M / Saur, Dieter / Schneider, Günter. ·Technische Universität München, Klinikum rechts der Isar, II, Medizinische Klinik, Ismaninger Str, 22, 81675 Munich, Germany. ·Mol Cancer · Pubmed #20398369.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions. RESULTS: Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells. CONCLUSIONS: Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.