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Pancreatic Neoplasms: HELP
Articles by Andrea S. Bauer
Based on 21 articles published since 2009
(Why 21 articles?)
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Between 2009 and 2019, A. Bauer wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Antimicrobial Peptide Human Neutrophil Peptide 1 as a Potential Link Between Chronic Inflammation and Ductal Adenocarcinoma of the Pancreas. 2018

Pausch, Thomas / Adolph, Sarah / Felix, Klaus / Bauer, Andrea S / Bergmann, Frank / Werner, Jens / Hartwig, Werner. · ·Pancreas · Pubmed #29683978.

ABSTRACT: OBJECTIVES: Defensins are antimicrobial peptides playing a role in innate immunity, in epithelial cell regeneration, and in carcinogenesis of inflammation-triggered malignancies. We analyzed this role in pancreatic ductal adenocarcinoma (PDAC) in the context of its association with chronic pancreatitis (CP). METHODS: Human tissue of healthy pancreas, CP, and PDAC was screened for defensins by immunohistochemistry. Defensin α 1 (human neutrophil peptide 1 [HNP-1]) expression was validated using mass spectrometry and microarray analysis. Human neutrophil peptide 1 expression and influences of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, and interferon γ) were studied in human pancreatic cancer cells (Colo 357, T3M4, PANC-1) and normal human pancreatic duct epithelial cells (HPDE). RESULTS: Accumulation of HNP-1 in malignant pancreatic ductal epithelia was seen. Spectrometry showed increased expression of HNP-1 in CP and even more in PDAC. At RNA level, no significant regulation was found. In cancer cells, HNP-1 expression was significantly higher than in HPDE. Proinflammatory cytokines significantly led to increased HNP-1 levels in culture supernatants and decreased levels in lysates of cancer cells. In HPDE cytokines significantly decreased HNP-1 levels. CONCLUSIONS: Inflammatory regulation of HNP-1 in PDAC tissue and cells indicates that HNP-1 may be a link between chronic inflammation and malignant transformation in the pancreas.

2 Article Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. 2018

Bauer, Andrea S / Nazarov, Petr V / Giese, Nathalia A / Beghelli, Stefania / Heller, Anette / Greenhalf, William / Costello, Eithne / Muller, Arnaud / Bier, Melanie / Strobel, Oliver / Hackert, Thilo / Vallar, Laurent / Scarpa, Aldo / Büchler, Markus W / Neoptolemos, John P / Kreis, Stephanie / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany. · Genomics and Proteomics Research Unit, Luxembourg Institute of Health, Luxembourg City, Luxembourg. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom. · Life Sciences Research Unit, University of Luxembourg, Luxembourg City, Luxembourg. ·Int J Cancer · Pubmed #28983920.

ABSTRACT: Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

3 Article Tumor cells interact with red blood cells via galectin-4 - a short report. 2017

Helwa, Reham / Heller, Anette / Knappskog, Stian / Bauer, Andrea S. ·Molecular Cell Biology Lab, Zoology Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt. reham.helwa@sci.asu.edu.eg. · Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. reham.helwa@sci.asu.edu.eg. · Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. reham.helwa@sci.asu.edu.eg. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. · Department of Oncology, Haukeland University Hospital, Bergen, Norway. · Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Cell Oncol (Dordr) · Pubmed #28293788.

ABSTRACT: BACKGROUND: The ability of tumor cells to invade and metastasize is relevant to the process of cancer progression and, as such, it represents an obstacle to cancer cure. So far, limited information is available on interactions between circulating tumor cells and blood cells. It is well-documented that galectin-4 is upregulated in many types of tumor cells and is involved in metastasis. Here, we address the hypothesis that tumor cells may interact with red blood cells (RBCs) via galectin-4. METHODS: High galectin-4 expressing colon, normal pancreatic and pancreatic cancer-derived cell lines (n = 5) were incubated with peripheral blood cells from different donors. Their interactions and associated proteins were examined by immunostaining and live cell imaging. RESULTS: We found that (endogenous or exogenous) galectin-4 expressing tumor cells interact directly with RBCs. We also observed an accumulation of galectin-4 and human blood group antigens at the contact sites between these cells. By comparing the number of RBCs attaching to each tumor cell, we found that cells with high pre-incubation expression levels of galectin-4 attached significantly more RBCs than those with low expression levels (p < 1 × 10 CONCLUSIONS: From our data we conclude that tumor cells directly interact with red blood cells via galectin-4.

4 Article Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice. 2016

Jandaghi, Pouria / Najafabadi, Hamed S / Bauer, Andrea S / Papadakis, Andreas I / Fassan, Matteo / Hall, Anita / Monast, Anie / von Knebel Doeberitz, Magnus / Neoptolemos, John P / Costello, Eithne / Greenhalf, William / Scarpa, Aldo / Sipos, Bence / Auld, Daniel / Lathrop, Mark / Park, Morag / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia A / Zogopoulos, George / Sangwan, Veena / Huang, Sidong / Riazalhosseini, Yasser / Hoheisel, Jörg D. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · Institute for Pathology and Neuropathology, Universitätsklinikum Tübingen, Tübingen, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montréal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. Electronic address: Yasser.riazalhosseini@mcgill.ca. ·Gastroenterology · Pubmed #27578530.

ABSTRACT: BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.

5 Article Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression. 2016

Botla, Sandeep K / Savant, Soniya / Jandaghi, Pouria / Bauer, Andrea S / Mücke, Oliver / Moskalev, Evgeny A / Neoptolemos, John P / Costello, Eithne / Greenhalf, William / Scarpa, Aldo / Gaida, Matthias M / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia A / Augustin, Hellmut G / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. · Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. · National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany. · Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.hoheisel@dkfz.de. ·Cancer Res · Pubmed #27216198.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.

6 Article Stratification of pancreatic tissue samples for molecular studies: RNA-based cellular annotation procedure. 2015

Heller, Anette / Gaida, Matthias M / Männle, D / Giese, Thomas / Scarpa, Aldo / Neoptolemos, John P / Hackert, Thilo / Strobel, Oliver / Hoheisel, Jörg D / Giese, Nathalia A / Bauer, Andrea S. ·Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: anette.heller@med.uni-heidelberg.de. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and ARC-NET Research Centre, University of Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, UK. · Functional Genome Analysis, German Research Cancer Center, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: nathalia.giese@med.uni-heidelberg.de. ·Pancreatology · Pubmed #26118650.

ABSTRACT: BACKGROUND/OBJECTIVES: Meaningful profiling of pancreatic cancer samples is particularly challenging due to their complex cellular composition. Beyond tumor cells, surgical biopsies contain desmoplastic stroma with infiltrating inflammatory cells, adjacent normal parenchyma, and "non-pancreatic tissues". The risk of misinterpretation rises when the heterogeneous cancer tissues are sub-divided into smaller fragments for multiple analytic procedures. Pre-analytic histological evaluation is the best option to characterize pancreatic tissue samples. Our aim was to develop a complement or alternative procedure to determine the cellular composition of pancreatic cancerous biopsies, basing on intra-analytic molecular annotation. A standard process for sample stratification at a molecular level does not yet exist. Particularly in the case of retrospective or data depository-based studies, when hematoxylin-eosin stained sections are not available, it supports the correct interpretation of expression profiles. METHODS: A five-gene transcriptional signature (RNACellStrat) was defined that allows cell type-specific stratification of pancreatic tissues. Testing biopsy material from biobanks with this procedure demonstrated high correspondence of molecular (qRT-PCR and microarray) and histologic (hematoxylin-eosin stain) evaluations. RESULTS: Notably, about a quarter of randomly selected samples (tissue fragments) were exposed as inappropriate for subsequent clinico-pathological interpretation. CONCLUSIONS: Via immediate intra-analytical procedure, our RNA-based stratification RNACellStrat increases the accuracy and reliability of the conclusions drawn from diagnostic and prognostic molecular information.

7 Article Transcriptional co-factor Transducin beta-like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy. 2015

Stoy, Christian / Sundaram, Aishwarya / Rios Garcia, Marcos / Wang, Xiaoyue / Seibert, Oksana / Zota, Annika / Wendler, Susann / Männle, David / Hinz, Ulf / Sticht, Carsten / Muciek, Maria / Gretz, Norbert / Rose, Adam J / Greiner, Vera / Hofmann, Thomas G / Bauer, Andrea / Hoheisel, Jörg / Berriel Diaz, Mauricio / Gaida, Matthias M / Werner, Jens / Schafmeier, Tobias / Strobel, Oliver / Herzig, Stephan. ·Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany. · Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Medical Research Center, Klinikum Mannheim, Mannheim, Germany. · Research Group Cellular Senescence, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. · Functional Genome Analysis, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. · Institute of Pathology Heidelberg University, Heidelberg, Germany. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de. · Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de. ·EMBO Mol Med · Pubmed #26070712.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.

8 Article GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers. 2015

Moskalev, Evgeny A / Jandaghi, Pouria / Fallah, Mahdi / Manoochehri, Mehdi / Botla, Sandeep K / Kolychev, Oleg V / Nikitin, Evgeny A / Bubnov, Vladymyr V / von Knebel Doeberitz, M / Strobel, Oliver / Hackert, Thilo / Büchler, Markus W / Giese, Nathalia / Bauer, Andrea / Muley, Thomas / Warth, Arne / Schirmacher, Peter / Haller, Florian / Hoheisel, Jörg D / Riazalhosseini, Yasser. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. · Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. · Molecular Genetic Epidemiology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. · Military Training Research Center, Zhukovsky - Gagarin Air Force Academy, Voronezh, Russia. · Molecular Haematology, National Research Centre for Haematology, Moscow, Russia. · Department of Genomics and Immunology, Odessa State Medical University, Odessa, Ukraine. · Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Translational Research Unit, Thoraxklinik Heidelberg at Heidelberg University, Heidelberg, Germany. · Department of Translational Pneumology, Translational Lung Research Centre Heidelberg (TLRC-H), Member of the German Centre for Lung Research (DZL), Heidelberg, Germany. · Institute of Pathology, University Hospital, Heidelberg, Germany. · Current address: Department of Human Genetics and McGill University and Genome Quebec Innovation Centre, Montreal, Quebec. ·Oncotarget · Pubmed #25557172.

ABSTRACT: Identification of a single molecular trait that is determinant of common malignancies may serve as a powerful diagnostic supplement to cancer type-specific markers. Here, we report a DNA methylation mark that is characteristic of seven studied malignancies, namely cancers of lung, breast, prostate, pancreas, colorectum, glioblastoma and B cell chronic lymphocytic leukaemia (CLL) (n = 137). This mark was defined by substantial hypermethylation at the promoter and first exon of growth hormone secretagouge receptor (GHSR) through bisulfite pyrosequencing. The degree of aberrant methylation was capable of accurate discrimination between cancer and control samples. The highest sensitivity and specificity of cancer detection was achieved for cancers of pancreas, lung, breast and CLL yielding the area under the curve (AUC) values of 1.0000, 0.9952, 0.9800 and 0.9400, respectively. Narrowing to a single CpG site within the gene's promoter or four consecutive CpG units of the highest methylation levels within the first exon improved the detection power. GHSR hypermethylation was detected already at the early stage tumors. The accurate performance of this marker was further replicated in an independent set of pancreatic cancer and control samples (n = 78). These findings support the candidature of GHSR methylation as a highly accurate pan-cancer marker.

9 Article Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors. 2014

Keleg, Shereen / Titov, Alexandr / Heller, Anette / Giese, Thomas / Tjaden, Christine / Ahmad, Sufian S / Gaida, Matthias M / Bauer, Andrea S / Werner, Jens / Giese, Nathalia A. ·European Pancreas Centre, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Functional Genomics, German Cancer Research Centre, Heidelberg, Germany. ·PLoS One · Pubmed #24932730.

ABSTRACT: CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high)/sera(low)-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.

10 Article Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. 2014

Dutruel, C / Bergmann, F / Rooman, I / Zucknick, M / Weichenhan, D / Geiselhart, L / Kaffenberger, T / Rachakonda, P S / Bauer, A / Giese, N / Hong, C / Xie, H / Costello, J F / Hoheisel, J / Kumar, R / Rehli, M / Schirmacher, P / Werner, J / Plass, C / Popanda, O / Schmezer, P. ·Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia. · Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. · Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. ·Oncogene · Pubmed #23912455.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway.

11 Article Somatic mutations in exocrine pancreatic tumors: association with patient survival. 2013

Rachakonda, P Sivaramakrishna / Bauer, Andrea S / Xie, Huaping / Campa, Daniele / Rizzato, Cosmeri / Canzian, Federico / Beghelli, Stefania / Greenhalf, William / Costello, Eithne / Schanne, Michaela / Heller, Anette / Scarpa, Aldo / Neoptolemos, John P / Werner, Jens / Büchler, Markus / Hoheisel, Jörg D / Hemminki, Kari / Giese, Nathalia / Kumar, Rajiv. ·Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. s.rachakonda@dkfz.de ·PLoS One · Pubmed #23565280.

ABSTRACT: KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.

12 Article ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium. 2013

Rizzato, Cosmeri / Campa, Daniele / Pezzilli, Raffaele / Soucek, Pavel / Greenhalf, William / Capurso, Gabriele / Talar-Wojnarowska, Renata / Heller, Anette / Jamroziak, Krzysztof / Khaw, Kay-Tee / Key, Tim J / Bambi, Franco / Landi, Stefano / Mohelnikova-Duchonova, Beatrice / Vodickova, Ludmila / Büchler, Markus W / Bugert, Peter / Vodicka, Pavel / Neoptolemos, John P / Werner, Jens / Hoheisel, Jörg D / Bauer, Andrea S / Giese, Nathalia / Canzian, Federico. ·Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Oncol Rep · Pubmed #23403949.

ABSTRACT: There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or B allele in comparison with the O allele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.

13 Article Lack of replication of seven pancreatic cancer susceptibility loci identified in two Asian populations. 2013

Campa, Daniele / Rizzato, Cosmeri / Bauer, Andrea S / Werner, Jens / Capurso, Gabriele / Costello, Eithne / Talar-Wojnarowska, Renata / Jamroziak, Krzysztof / Pezzilli, Raffaele / Gazouli, Maria / Khaw, Kay-Tee / Key, Timothy J / Bambi, Franco / Mohelnikova-Duchonova, Beatrice / Heller, Anette / Landi, Stefano / Vodickova, Ludmila / Theodoropoulos, George / Bugert, Peter / Vodicka, Pavel / Hoheisel, Jörg D / Delle Fave, Gianfranco / Neoptolemos, John P / Soucek, Pavel / Büchler, Markus W / Giese, Nathalia / Canzian, Federico. ·German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Cancer Epidemiol Biomarkers Prev · Pubmed #23250936.

ABSTRACT: BACKGROUND: Two recent genome-wide association studies (GWAS) of pancreatic ductal adenocarcinoma (PDAC), conducted, respectively, in a Japanese and in a Chinese population, identified eight novel loci affecting PDAC risk. METHODS: We attempted to replicate the novel loci in a series of PDACs and healthy controls of European ancestry in the context of the newly formed PANcreatic Disease ReseArch (PANDoRA) consortium. We genotyped seven single-nucleotide polymorphisms (SNP): rs12413624, rs1547374, rs372883, rs5768709, rs6464375, rs708224, rs9502893 (one SNP identified in the Chinese GWAS is not polymorphic in Caucasians) in 1,299 PDAC cases and 2,884 controls. We also attempted stratified analysis considering the different stages of the disease and addressed the possible involvement of the selected SNPs on the survival of patients. RESULTS: None of the SNPs were significantly associated with PDAC risk if considering the overall population of the consortium. When stratifying for country of origin, we found that in the Polish subgroup, the G allele of rs372883 was statistically significantly associated with increased risk [OR, 6.40; 95% confidence interval (CI), 2.28-17.91]. However, the sample size of the subgroups was rather small; therefore, this result can be due to chance. None of the SNPs was associated with disease progression or survival. CONCLUSIONS: None of the SNPs associated with PDAC risk in two Asian populations were convincingly associated with PDAC risk in individuals of European descent. IMPACT: This study illustrates the importance of evaluation of PDAC risk markers across ethnic groups.

14 Article Immunoassay-based proteome profiling of 24 pancreatic cancer cell lines. 2012

Alhamdani, Mohamed Saiel Saeed / Youns, Mahmoud / Buchholz, Malte / Gress, Thomas M / Beckers, Marie-Claire / Maréchal, Daniel / Bauer, Andrea / Schröder, Christoph / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, Heidelberg, Germany. m.alhamdani@dkfz.de ·J Proteomics · Pubmed #22579748.

ABSTRACT: Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers, with a mortality that is almost identical to incidence. The inability to predict, detect or diagnose the disease early and its resistance to all current treatment modalities but surgery are the prime challenges to changing the devastating prognosis. Also, relatively little is known about pancreatic carcinogenesis. In order to better understand relevant aspects of pathophysiology, differentiation, and transformation, we analysed the cellular proteomes of 24 pancreatic cancer cell lines and two controls using an antibody microarray that targets 741 cancer-related proteins. In this analysis, 72 distinct disease marker proteins were identified that had not been described before. Additionally, categorizing cancer cells in accordance to their original location (primary tumour, liver metastases, or ascites) was made possible. A comparison of the cells' degree of differentiation (well, moderately, or poorly differentiated) resulted in unique marker sets of high relevance. Last, 187 proteins were differentially expressed in primary versus metastatic cancer cells, of which the majority is functionally related to cellular movement.

15 Article Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue. 2012

Bauer, Andrea S / Keller, Andreas / Costello, Eithne / Greenhalf, William / Bier, Melanie / Borries, Anne / Beier, Markus / Neoptolemos, John / Büchler, Markus / Werner, Jens / Giese, Nathalia / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. ·PLoS One · Pubmed #22511932.

ABSTRACT: A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer.

16 Article Pancreatic cancer susceptibility loci and their role in survival. 2011

Rizzato, Cosmeri / Campa, Daniele / Giese, Nathalia / Werner, Jens / Rachakonda, P Sivaramakrishna / Kumar, Rajiv / Schanné, Michaela / Greenhalf, William / Costello, Eithne / Khaw, Kay-Tee / Key, Tim J / Siddiq, Afshan / Lorenzo-Bermejo, Justo / Burwinkel, Barbara / Neoptolemos, John P / Büchler, Markus W / Hoheisel, Jörg D / Bauer, Andrea / Canzian, Federico. ·German Cancer Research Center-DKFZ, Heidelberg, Germany. ·PLoS One · Pubmed #22125638.

ABSTRACT: Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.

17 Article Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). 2011

Holtrup, Frank / Bauer, Andrea / Fellenberg, Kurt / Hilger, Ralf A / Wink, Michael / Hoheisel, Jörg D. ·Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany. f.holtrup@dkfz.de ·Br J Pharmacol · Pubmed #21091652.

ABSTRACT: BACKGROUND AND PURPOSE: Pancreatic cancer is one of the leading cancer-related causes of death due to high chemo-resistance and fast metastasation. Nemorosone, a polycyclic polyprenylated acylphloroglucinol, has recently been identified as a promising anticancer agent. Here, we examine its growth-inhibitory effects on pancreatic cancer cells. Based on transcription profiling, a molecular mode of action is proposed. EXPERIMENTAL APPROACH: Nemorosone cytotoxicity was assessed by the resazurin proliferation assay on pancreatic cancer cells and fibroblasts. Apoptosis was determined by Annexin V/propidium iodide staining as well as cytochrome c and caspase activation assays. Staining with the voltage-dependent dye JC-1 and fluorescence microscopy were used to detect effects on mitochondrial membrane potential. Total RNA was isolated from treated cell lines and subjected to microarray analysis, subsequent pathway identification and modelling. Gene expression data were validated by quantitative polymerase chain reaction and siRNA-mediated gene knock-down. KEY RESULTS: Nemorosone significantly inhibited cancer cell growth, induced cytochrome c release and subsequent caspase-dependent apoptosis, rapidly abolished mitochondrial membrane potential and elevated cytosolic calcium levels, while fibroblasts were largely unaffected. Expression profiling revealed 336 genes to be affected by nemorosone. A total of 75 genes were altered in all three cell lines, many of which were within the unfolded protein response (UPR) network. DNA damage inducible transcript 3 was identified as a key regulator in UPR-mediated cell death. CONCLUSIONS AND IMPLICATIONS: Nemorosone could be a lead compound for the development of novel anticancer drugs amplifying the already elevated UPR level in solid tumours, thus driving them into apoptosis. This study forms the basis for further investigations identifying nemorosone's direct molecular target(s).

18 Article Dual-color proteomic profiling of complex samples with a microarray of 810 cancer-related antibodies. 2010

Schröder, Christoph / Jacob, Anette / Tonack, Sarah / Radon, Tomasz P / Sill, Martin / Zucknick, Manuela / Rüffer, Sven / Costello, Eithne / Neoptolemos, John P / Crnogorac-Jurcevic, Tatjana / Bauer, Andrea / Fellenberg, Kurt / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany. christoph.schroeder@dkfz.de ·Mol Cell Proteomics · Pubmed #20164060.

ABSTRACT: Antibody microarrays have the potential to enable comprehensive proteomic analysis of small amounts of sample material. Here, protocols are presented for the production, quality assessment, and reproducible application of antibody microarrays in a two-color mode with an array of 1,800 features, representing 810 antibodies that were directed at 741 cancer-related proteins. In addition to measures of array quality, we implemented indicators for the accuracy and significance of dual-color detection. Dual-color measurements outperform a single-color approach concerning assay reproducibility and discriminative power. In the analysis of serum samples, depletion of high-abundance proteins did not improve technical assay quality. On the contrary, depletion introduced a strong bias in protein representation. In an initial study, we demonstrated the applicability of the protocols to proteins derived from urine samples. We identified differences between urine samples from pancreatic cancer patients and healthy subjects and between sexes. This study demonstrates that biomedically relevant data can be produced. As demonstrated by the thorough quality analysis, the dual-color antibody array approach proved to be competitive with other proteomic techniques and comparable in performance to transcriptional microarray analyses.

19 Article Subcellular protein extraction from human pancreatic cancer tissues. 2009

Börner, Anette / Warnken, Uwe / Schnölzer, Martina / Hagen, Jörg von / Giese, Nathalia / Bauer, Andrea / Hoheisel, Jörg. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. a.boerner@dkfz.de ·Biotechniques · Pubmed #19450236.

ABSTRACT: Proteins are the major class of effector molecules in cellular systems. For the identification of functional differences between normal and diseased tissues, a reliable analysis of their protein content is essential. Reproducible isolation and fractionation of intact proteins are important in this respect, but their complexity in structure and concentration, their close interaction, and their instability represent major challenges. For protein isolation in tissues, the breakdown of cell-cell and cell-matrix connections within a tissue without affecting protein quality is a critical factor. We compared different processes for a compartmental protein preparation from pancreatic tissue, one of the most challenging tissues for protein isolation because of its high protease content. Success of the different procedures varied greatly. Based on a scheme of tissue-slicing and subsequent cell isolation, we established a reliable workflow for the fractional extraction of cytosolic proteins, membrane and organelle proteins, nuclear proteins, and cytoskeletal filaments. The tissue slices also allow for a representative confirmation of individual samples' cellular status by histochemical processes, and a proper separation or mixing of cellular material from across a tumor if required.

20 Article Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells. 2009

Youns, Mahmoud / Efferth, Thomas / Reichling, Jürgen / Fellenberg, Kurt / Bauer, Andrea / Hoheisel, Jörg D. ·Department of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. m.youns@dkfz.de ·Biochem Pharmacol · Pubmed #19393226.

ABSTRACT: Pancreatic cancer is one of the most aggressive human malignancies, with an extremely poor prognosis. The paucity of curative therapies has translated into an overall 5-year survival rate of less than 5%, underscoring a desperate need for new therapeutic options. Artesunate (ART), clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity. However, the mechanisms underlying those activities in pancreatic cancer are not yet known. Here we evaluated the anti-tumor activity of Artesunate and the possible underlying mechanisms in pancreatic cancer. MiaPaCa-2 (poorly differentiated) and BxPC-3 (moderately differentiated) pancreatic cancer cell lines were treated with Artesunate and the effect was monitored by a tetrazolium-based assay (MTS) for evaluating cell viability and by flow cytometry and caspase 3/7 activation for apoptosis evaluation. In addition cDNA arrays were used to identify differentially expressed genes. The microarray data were then validated by RT-PCR and Western blotting. Moreover, pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis. The expression analysis identified a common set of genes that were regulated by Artesunate in pancreatic cancer. Our results provide the first in vitro evidence for the therapeutic utility of Artesunate in pancreatic cancer. Moreover, we identified Artesunate as a novel topoisomerase IIalpha inhibitor that inhibits pancreatic cancer growth through modulation of multiple signaling pathways. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of Artesunate in tumor cells.

21 Article Neuromedin U is overexpressed in pancreatic cancer and increases invasiveness via the hepatocyte growth factor c-Met pathway. 2009

Ketterer, Knut / Kong, Bo / Frank, Dietwalt / Giese, Nathalia A / Bauer, Andrea / Hoheisel, Jörg / Korc, Murray / Kleeff, Jörg / Michalski, Christoph W / Friess, Helmut. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, Munich, Germany. ·Cancer Lett · Pubmed #19118941.

ABSTRACT: Neuromedin U (NmU) is a bioactive peptide, ubiquitously expressed in the gastrointestinal tract. Here, we analyzed the role of NmU in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. NmU and NmU receptor-2 mRNA were significantly overexpressed in PDAC and in metastatic tissues. NmU and NmU receptor-2 were localized predominantly in cancer cells. NmU serum levels decreased after tumor resection. Although NmU exerted no effects on cancer cell proliferation, it induced c-Met and a trend towards increased invasiveness as well as an increased hepatocyte growth factor (HGF)-mediated scattering. Thus, NmU may be involved in the HGF-c-Met paracrine loop regulating cell migration, invasiveness and dissemination of PDAC.