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Pancreatic Neoplasms: HELP
Articles by Frank Ulrich Weiss
Based on 20 articles published since 2009
(Why 20 articles?)
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Between 2009 and 2019, F. Weiss wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. 2013

McCleary-Wheeler, Angela L / Lomberk, Gwen A / Weiss, Frank U / Schneider, Günter / Fabbri, Muller / Poshusta, Tara L / Dusetti, Nelson J / Baumgart, Sandra / Iovanna, Juan L / Ellenrieder, Volker / Urrutia, Raul / Fernandez-Zapico, Martin E. ·Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Rochester, MN, USA. ·Cancer Lett · Pubmed #23073473.

ABSTRACT: During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.

2 Review Environmental risk factors for chronic pancreatitis and pancreatic cancer. 2011

Nitsche, Claudia / Simon, Peter / Weiss, F Ulrich / Fluhr, Gabriele / Weber, Eckhard / Gärtner, Simone / Behn, Claas O / Kraft, Matthias / Ringel, Jörg / Aghdassi, Ali / Mayerle, Julia / Lerch, Markus M. ·Department of Medicine A, Klinikum der Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. ·Dig Dis · Pubmed #21734390.

ABSTRACT: Chronic pancreatitis has long been thought to be mainly associated with immoderate alcohol consumption. The observation that only ∼10% of heavy drinkers develop chronic pancreatitis not only suggests that other environmental factors, such as tobacco smoke, are potent additional risk factors, but also that the genetic component of pancreatitis is more common than previously presumed. Either disease-causing or protective traits have been indentified for mutations in different trypsinogen genes, the gene for the trypsin inhibitor SPINK1, chymotrypsinogen C, and the cystic fibrosis transmembane conductance regulator (CFTR). Other factors that have been proposed to contribute to pancreatitis are obesity, diets high in animal protein and fat, as well as antioxidant deficiencies. For the development of pancreatic cancer, preexisting chronic pancreatitis, more prominently hereditary pancreatitis, is a risk factor. The data on environmental risk factors for pancreatic cancer are, with the notable exception of tobacco smoke, either sparse, unconfirmed or controversial. Obesity appears to increase the risk of pancreatic cancer in the West but not in Japan. Diets high in processed or red meat, diets low in fruits and vegetables, phytochemicals such as lycopene and flavonols, have been proposed and refuted as risk or protective factors in different trials. The best established and single most important risk factor for cancer as well as pancreatitis and the one to clearly avoid is tobacco smoke.

3 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

4 Article Plasma protein profiling of patients with intraductal papillary mucinous neoplasm of the pancreas as potential precursor lesions of pancreatic cancer. 2018

Ilies, Maria / Sappa, Praveen Kumar / Iuga, Cristina Adela / Loghin, Felicia / Gesell Salazar, Manuela / Weiss, Frank Ulrich / Beyer, Georg / Lerch, Markus M / Völker, Uwe / Mayerle, Julia / Hammer, Elke. ·Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania; Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: ilies.maria@umfcluj.ro. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: praveen.kumar@uni-greifswald.de. · Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania; Department of Proteomics and Metabolomics, MedFuture Research Center for Advanced Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, no. 4-6 Louis Pasteur st., 400349 Cluj-Napoca, Romania. Electronic address: iugac@umfcluj.ro. · Department of Toxicology, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania. Electronic address: floghin@umfcluj.ro. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: gesell@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany. Electronic address: ulrich.weiss@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany; Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377 München, Germany. Electronic address: georg.beyer@med.uni-muenchen.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany. Electronic address: lerch@uni-greifswald.de. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: voelker@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany; Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377 München, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: hammer@uni-greifswald.de. ·Clin Chim Acta · Pubmed #29221926.

ABSTRACT: Efforts for the early diagnosis of the pancreatic ductal adenocarcinoma (PDAC) have recently been driven to one of the precursor lesions, namely intraductal papillary mucinous neoplasm of the pancreas (IPMN). Only a few studies have focused on IPMN molecular biology and its overall progression to cancer. Therefore, IPMN lacks comprehensive characterization which makes its clinical management controversial. In this study, we characterized plasma proteins in the presence of IPMNs in comparison to healthy controls, chronic pancreatitis, and PDAC by a proteomics approach using data-independent acquisition based mass spectrometry. We describe several protein sets that could aid IPMN diagnosis, but also differentiation of IPMN from healthy controls, as well as from benign and malignant diseases. Among all, high levels of carbonic anhydrases and hemoglobins were characteristic for the IPMN group. By employing ELISA based quantification we validated our results for human tissue inhibitor of metalloproteinase inhibitor 1 (TIMP-1). We consider IPMN management directed towards an early potential cancer development a crucial opportunity before PDAC initiation and thus its early detection and cure.

5 Article Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. 2018

Mayerle, Julia / Kalthoff, Holger / Reszka, Regina / Kamlage, Beate / Peter, Erik / Schniewind, Bodo / González Maldonado, Sandra / Pilarsky, Christian / Heidecke, Claus-Dieter / Schatz, Philipp / Distler, Marius / Scheiber, Jonas A / Mahajan, Ujjwal M / Weiss, F Ulrich / Grützmann, Robert / Lerch, Markus M. ·Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, München, Germany. · Section for Molecular Oncology, Institut for Experimental Cancer Research (IET), UKSH, Kiel, Germany. · Metanomics Health GmbH, Berlin, Germany. · metanomics GmbH, Berlin, Germany. · Department of Surgery, University Hospital, Erlangen, Germany. · Department of General, Visceral, Thoracic and Vascular Surgery University Medicine Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. · Clinic and Outpatient Clinic for Visceral-, Thorax- and Vascular Surgery, Medizinische Fakultät, TU Dresden, Dresden, Germany. ·Gut · Pubmed #28108468.

ABSTRACT: OBJECTIVE: Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. DESIGN: For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. CONCLUSIONS: In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.

6 Article Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFα in a murine pancreatic cancer model. 2017

Partecke, Lars Ivo / Käding, André / Trung, Dung Nguyen / Diedrich, Stephan / Sendler, Matthias / Weiss, Frank / Kühn, Jens-Peter / Mayerle, Julia / Beyer, Katharina / von Bernstorff, Wolfram / Heidecke, Claus-Dieter / Keßler, Wolfram. ·Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany. · Department of Internal Medicine A, University Medicine, Greifswald, Germany. · Department of Experimental Radiology, University Medicine, Greifswald, Germany. · Department of General, Visceral and Vascular Surgery, Charité-University Medicine, Campus Benjamin Franklin, Berlin, Germany (current address). ·Oncotarget · Pubmed #28160574.

ABSTRACT: This study analyses the effects of vagotomy on tumor growth and survival in a murine, pancreatic cancer model in wild-type and TNFα-knockout (-/-) mice.Throughout many operative procedures in the upper gastrointestinal tract the partial or complete transection of the vagus nerve or its local nerve fibers is unavoidable. Thereby its anti-inflammatory effects in residual tumor tissue may get lost. This effect may be mediated by tumor-associated macrophages (TAM) secreting TNFα.In an orthotopic murine pancreatic cancer model subdiaphragmatic vagotomy versus sham surgery was performed. The impact on tumor growth was monitored in wild type and TNFα -/- mice using MRI. TAMs as well as expression levels of TNFα were analyzed using immunohistochemistry. The role of TNFα on tumor growth and migration was examined in vitro. Vagotomised mice showed increased tumor growth with macroscopic features of invasive growth and had a shorter survival time. The loss of vagal modulation led to significantly increased TNFα levels in tumors and considerably elevated numbers of TAMs. In vitro TNFα significantly stimulated growth (p < 0.05) and migration (p < 0.05) of pancreatic cancer cells. TNFα -/- mice survived significantly longer after tumor implantation (p < 0.05), with vagotomy not affecting the prognosis of these animals (p > 0.05).Vagotomy can increase tumor growth and worsen survival in a murine pancreatic cancer model mediated through TAMs and TNFα. Hence, the suppression of TAMs and the modulation of TNFα dependent pathways could offer new perspectives in immunotherapies of pancreatic cancer patients especially with remaining vital tumor cells and lost vagal modulation.

7 Article Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. 2017

Dalva, Monica / El Jellas, Khadija / Steine, Solrun J / Johansson, Bente B / Ringdal, Monika / Torsvik, Janniche / Immervoll, Heike / Hoem, Dag / Laemmerhirt, Felix / Simon, Peter / Lerch, Markus M / Johansson, Stefan / Njølstad, Pål R / Weiss, Frank U / Fjeld, Karianne / Molven, Anders. ·KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. · KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway. · Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. · KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. · KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. · Department of Pathology, Haukeland University Hospital, Bergen, Norway. · Department of Gastrointestinal Surgery, Haukeland University Hospital, Bergen, Norway. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway. · KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Electronic address: karianne.fjeld@uib.no. ·Pancreatology · Pubmed #27773618.

ABSTRACT: BACKGROUND/OBJECTIVES: We have recently described copy number variants (CNVs) of the human carboxyl-ester lipase (CEL) gene, including a recombined deletion allele (CEL-HYB) that is a genetic risk factor for chronic pancreatitis. Associations with pancreatic disease have also been reported for the variable number of tandem repeat (VNTR) region located in CEL exon 11. Here, we examined if CEL CNVs and VNTR length polymorphisms affect the risk for developing pancreatic cancer. METHODS: CEL CNVs and VNTR were genotyped in a German family with non-alcoholic chronic pancreatitis and pancreatic cancer, in 265 German and 197 Norwegian patients diagnosed with pancreatic adenocarcinoma, and in 882 controls. CNV screening was performed using PCR assays followed by agarose gel electrophoresis whereas VNTR lengths were determined by DNA fragment analysis. RESULTS: The investigated family was CEL-HYB-positive. However, an association of CEL-HYB or a duplication CEL allele with pancreatic cancer was not seen in our two patient cohorts. The frequency of the 23-repeat VNTR allele was borderline significant in Norwegian cases compared to controls (1.2% vs. 0.3%; P = 0.05). For all other VNTR lengths, no statistically significant difference in frequency was observed. Moreover, no association with pancreatic cancer was detected when CEL VNTR lengths were pooled into groups of short, normal or long alleles. CONCLUSIONS: We could not demonstrate an association between CEL CNVs and pancreatic cancer. An association is also unlikely for CEL VNTR lengths, although analyses in larger materials are necessary to completely exclude an effect of rare VNTR alleles.

8 Article Development of Pancreatic Cancer: Targets for Early Detection and Treatment. 2016

Lerch, Markus M / Mayerle, Julia / Mahajan, Ujjwal / Sendler, Matthias / Weiss, F Ulrich / Aghdassi, Ali / Moskwa, Patryk / Simon, Peter. ·Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. ·Dig Dis · Pubmed #27332960.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. KEY MESSAGES: Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. CONCLUSIONS: Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized.

9 Article Tumour-specific delivery of siRNA-coupled superparamagnetic iron oxide nanoparticles, targeted against PLK1, stops progression of pancreatic cancer. 2016

Mahajan, Ujjwal M / Teller, Steffen / Sendler, Matthias / Palankar, Raghavendra / van den Brandt, Cindy / Schwaiger, Theresa / Kühn, Jens-Peter / Ribback, Silvia / Glöckl, Gunnar / Evert, Matthias / Weitschies, Werner / Hosten, Norbert / Dombrowski, Frank / Delcea, Mihaela / Weiss, Frank-Ulrich / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. · ZIK HIKE-Center for Innovation Competence Humoral Immune Reactions in Cardiovascular Diseases, Greifswald, Germany. · Department of Radiology and Neuroradiology, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Institute of Pathology, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. · Institute of Pharmacy, Ernst-Moritz-Arndt-University, Greifswald, Germany. ·Gut · Pubmed #27196585.

ABSTRACT: OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is projected to be the second leading cause of cancer-related death by 2030. Despite extensive knowledge and insights into biological properties and genetic aberrations of PDAC, therapeutic options remain temporary and ineffective. One plausible explanation for the futile response to therapy is an insufficient and non-specific delivery of anticancer drugs to the tumour site. DESIGN: Superparamagnetic iron oxide nanoparticles (SPIONs) coupled with siRNA directed against the cell cycle-specific serine-threonine-kinase, Polo-like kinase-1 (siPLK1-StAv-SPIONs), could serve a dual purpose for delivery of siPLK1 to the tumour and for non-invasive assessment of efficiency of delivery in vivo by imaging the tumour response. siPLK1-StAv-SPIONs were designed and synthesised as theranostics to function via a membrane translocation peptide with added advantage of driving endosomal escape for mediating transportation to the cytoplasm (myristoylated polyarginine peptides) as well as a tumour-selective peptide (EPPT1) to increase intracellular delivery and tumour specificity, respectively. RESULTS: A syngeneic orthotopic as well as an endogenous cancer model was treated biweekly with siPLK1-StAv-SPIONs and tumour growth was monitored by small animal MRI. In vitro and in vivo experiments using a syngeneic orthotopic PDAC model as well as the endogenous LSL-Kras CONCLUSIONS: Our data suggest siPLK1-StAv-SPIONs with dual specificity residues for tumour targeting and membrane translocation to represent an exciting opportunity for targeted therapy in patients with PDAC.

10 Article Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade. 2016

Partecke, Lars Ivo / Speerforck, Sven / Käding, André / Seubert, Florian / Kühn, Sandra / Lorenz, Eric / Schwandke, Sebastian / Sendler, Matthias / Keßler, Wolfram / Trung, Dung Nguyen / Oswald, Stefan / Weiss, Frank Ulrich / Mayerle, Julia / Henkel, Christin / Menges, Pia / Beyer, Katharina / Lerch, Markus M / Heidecke, Claus-Dieter / von Bernstorff, Wolfram. ·Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. · Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. · Institute of Pharmacology, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. · Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. Electronic address: wolfram.bernstorff@uni-greifswald.de. ·Pancreatology · Pubmed #27083074.

ABSTRACT: BACKGROUND/OBJECTIVES: Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer. METHODS AND RESULTS: Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p = 0.0138) higher circulating steroid and 111% (p = 0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The in vitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011 < p < 0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p > 0.05). TGF-beta in vitro was increased by 23.4% using catecholamines (p < 0.012) and in vivo employing chronic stress (p < 0.001). After 5 weeks tumour volumes were 130% (p = 0.0061) larger and median survival reduced by 13.5% (p = 0.0058). Tumours expressed more VEGF (p = 0.0334), had greater microvessel densities (p = 0.047), and an increased MMP-9 expression (p = 0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p < 0.0001) and migration by 78% (p = 0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p < 0.0001) and 53% (p = 0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p = 0.0088) and survival improved by 14% (p < 0.0058). CONCLUSIONS: The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.

11 Article Surgical trauma leads to a shorter survival in a murine orthotopic pancreatic cancer model. 2015

Menges, Pia / Klöcker, Christian / Diedrich, Stephan / Sendler, Matthias / Maier, Stefan / Weiss, Frank-Ulrich / Heidecke, Claus-Dieter / von Bernstorff, Wolfram / Partecke, Lars Ivo. ·Division of General Surgery, Visceral, Thoracic and Vascular Surgery, Department of Surgery, University Medicine Greifswald, Greifswald, Germany. ·Eur Surg Res · Pubmed #25402012.

ABSTRACT: BACKGROUND: Abdominal surgery is frequently followed by immune dysfunction usually lasting for several days. This is especially important in cases with tumour diseases as an intact immune function is essential in this situation. Therefore, we analysed the outcome of tumour-bearing mice in a mouse model of surgically induced immune dysfunction (SID). METHODS: In male C57BL/6 mice, a pancreatic tumour was implanted orthotopically. Following tumour implantation, the model of SID was applied. The control groups were either laparotomised or underwent no surgical procedure. The survival rate was determined by observation for >60 days. The tumour growth progress was imaged by a 7-tesla small animal MRI. RESULTS: On day 60 after tumour implantation, the survival rate in SID mice was reduced to 41%. In the laparotomised group, 81% of mice survived, while the control group had a survival rate of 75%. These differences were significant (SID vs. control: p < 0.02, and SID vs. laparotomy: p < 0.002). The tumour volume was not influenced by the degree of surgical trauma. CONCLUSION: In pancreatic cancer, the SID model is ideally suited to investigate the influence of SID on this tumour entity.

12 Article Induction of M2-macrophages by tumour cells and tumour growth promotion by M2-macrophages: a quid pro quo in pancreatic cancer. 2013

Partecke, L I / Günther, C / Hagemann, S / Jacobi, C / Merkel, M / Sendler, M / van Rooijen, N / Käding, A / Nguyen Trung, D / Lorenz, E / Diedrich, S / Weiss, F U / Heidecke, C D / von Bernstorff, W. ·Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine Greifswald, Ernst-Moritz-Arndt-University, Ferdinand Sauerbruchstraße, 17475 Greifswald, Germany. Electronic address: partecke@uni-greifswald.de. ·Pancreatology · Pubmed #24075516.

ABSTRACT: INTRODUCTION: More effective therapies are required to improve survival of pancreatic cancer. Possible immunologic targets include tumour associated macrophages (TAMs), generally consisting of M1- and M2-macrophages. We have analysed the impact of TAMS on pancreatic cancer in a syngeneic orthotopic murine model. METHODS: 6606PDA murine pancreatic cancer cells were orthotopically injected into C57BL6 mice. Tumour growth was monitored using MRI. Macrophages were depleted by clodronate liposomes. Tumours including microvessel density were evaluated using immunohistochemistry, immunofluorescence and/or cytometric beads assays. Naïve macrophages were generated employing peritoneal macrophages. In vitro experiments included culturing of macrophages in tumour supernatants as well as tumour cells cultured in macrophage supernatants using arginase as well as Griess assays. RESULTS: Clodronate treatment depleted macrophages by 80% in livers (p = 0.0051) and by 60% in pancreatic tumours (p = 0.0169). MRI revealed tumour growth inhibition from 221.8 mm(3) to 92.3 mm(3) (p = 0.0216). Micro vessel densities were decreased by 44% (p = 0.0315). Yet, MCP-1-, IL-4- and IL-10-levels within pancreatic tumours were unchanged. 6606PDA culture supernatants led to a shift from naïve macrophages towards an M2-phenotype after a 36 h treatment (p < 0.0001), reducing M1-macrophages at the same time (p < 0.037). In vivo, M2-macrophages represented 85% of all TAMs (p < 0.0001). Finally, culture supernatants of M2-macrophages induced tumour growth in vitro by 63.2% (p = 0.0034). CONCLUSIONS: This quid pro quo of tumour cells and M2-macrophages could serve as a new target for future immunotherapies that interrupt tumour promoting activities of TAMs and change the iNOS-arginase balance towards their tumoricidal capacities.

13 Article Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for pancreatic and colorectal adenocarcinoma. 2013

Baraniskin, Alexander / Nöpel-Dünnebacke, Stefanie / Ahrens, Maike / Jensen, Steffen Grann / Zöllner, Hannah / Maghnouj, Abdelouahid / Wos, Alexandra / Mayerle, Julia / Munding, Johanna / Kost, Dennis / Reinacher-Schick, Anke / Liffers, Sven / Schroers, Roland / Chromik, Ansgar M / Meyer, Helmut E / Uhl, Waldemar / Klein-Scory, Susanne / Weiss, Frank U / Stephan, Christian / Schwarte-Waldhoff, Irmgard / Lerch, Markus M / Tannapfel, Andrea / Schmiegel, Wolff / Andersen, Claus Lindbjerg / Hahn, Stephan A. ·Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. ·Int J Cancer · Pubmed #22907602.

ABSTRACT: Improved non-invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non-coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as biomarkers for non-invasive cancer diagnosis. Analyzing serum derived from nude mice implanted with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR-1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR-1246 assays with RNA fragments derived from U2 small nuclear RNA (RNU2-1). Importantly, we found that the assay signal discriminating tumor from controls was derived from U2 small nuclear RNA (snRNA) fragments (RNU2-1f) and not from miR-1246. In addition, we observed a remarkable stability of RNU2-1f in serum and provide experimental evidence that hsa-miR-1246 is likely a pseudo microRNA. In a next step, RNU2-1f was measured by qRT-PCR and normalized to cel-54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity and specificity of 97.7% [95% CI = (87.7, 99.9)] and 90.6% [95% CI = (80.7, 96.5)], respectively [area under the ROC curve 0.972]. Of note, patients with CRC were detected with our assay as early as UICC Stage II with a sensitivity of 81%. In conclusion, this is the first report showing that fragments of U2 snRNA are highly stable in serum and plasma and may serve as novel diagnostic biomarker for PDAC and CRC for future prospective screening studies.

14 Article Tissue tolerable plasma (TTP) induces apoptosis in pancreatic cancer cells in vitro and in vivo. 2012

Partecke, Lars Ivo / Evert, Katja / Haugk, Jan / Doering, Friderike / Normann, Lars / Diedrich, Stephan / Weiss, Frank-Ulrich / Evert, Matthias / Huebner, Nils Olaf / Guenther, Cristin / Heidecke, Claus Dieter / Kramer, Axel / Bussiahn, René / Weltmann, Klaus-Dieter / Pati, Onur / Bender, Claudia / von Bernstorff, Wolfram. ·Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. partecke@uni-greifswald.de ·BMC Cancer · Pubmed #23066891.

ABSTRACT: BACKGROUND: The rate of microscopic incomplete resections of gastrointestinal cancers including pancreatic cancer has not changed considerably over the past years. Future intra-operative applications of tissue tolerable plasmas (TTP) could help to address this problem. Plasma is generated by feeding energy, like electrical discharges, to gases. The development of non-thermal atmospheric plasmas displaying spectra of temperature within or just above physiological ranges allows biological or medical applications of plasmas. METHODS: We have investigated the effects of tissue tolerable plasmas (TTP) on the human pancreatic cancer cell line Colo-357 and PaTu8988T and the murine cell line 6606PDA in vitro (Annexin-V-FITC/DAPI-Assay and propidium iodide DNA staining assay) as well as in the in vivo tumour chorio-allantoic membrane (TUM-CAM) assay using Colo-357. RESULTS: TTP of 20 seconds (s) induced a mild elevation of an experimental surface temperature of 23.7 degree Celsius up to 26.63+/-0.40 degree Celsius. In vitro TTP significantly (p=0.0003) decreased cell viability showing the strongest effects after 20s TTP. Also, TTP effects increased over time levelling off after 72 hours (30.1+/-4.4% of dead cells (untreated control) versus 78.0+/-9.6% (20s TTP)). However, analyzing these cells for apoptosis 10s TTP revealed the largest proportion of apoptotic cells (34.8+/-7.2%, p=0.0009 versus 12.3+/-6.6%, 20s TTP) suggesting non-apoptotic cell death in the majority of cells after 20s TTP. Using solid Colo-357 tumours in the TUM-CAM model TUNEL-staining showed TTP-induced apoptosis up to a depth of tissue penetration (DETiP) of 48.8+/-12.3μm (20s TTP, p<0.0001). This was mirrored by a significant (p<0.0001) reduction of Ki-67+ proliferating cells (80.9+/-13.2% versus 37.7+/-14.6%, p<0.0001) in the top cell layers as well as typical changes on HE specimens. The bottom cell layers were not affected by TTP. CONCLUSIONS: Our data suggest possible future intra-operative applications of TTP to reduce microscopic residual disease in pancreatic cancer resections. Further promising applications include other malignancies (central liver/lung tumours) as well as synergistic effects combining TTP with chemotherapies. Yet, adaptations of plasma sources as well as of the composition of effective components of TTP are required to optimize their synergistic apoptotic actions.

15 Article Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. 2012

Aghdassi, Ali / Sendler, Matthias / Guenther, Annett / Mayerle, Julia / Behn, Claas-Olsen / Heidecke, Claus-Dieter / Friess, Helmut / Büchler, Markus / Evert, Matthias / Lerch, Markus M / Weiss, Frank Ulrich. ·Department of Medicine A, Ernst-Moritz-Arndt Universität Greifswald, Friedrich-Loefler-Str. 23a, 17475 Greifswald, Germany. ·Gut · Pubmed #22147512.

ABSTRACT: OBJECTIVE: Pancreatic cancer is characterised by invasive tumour spread and early metastasis formation. During epithelial-mesenchymal transition, loss of the cell adhesion molecule E-cadherin is frequent and can be caused by genetic or epigenetic modifications, recruitment of transcriptional activators/repressors or post-translational modifications. A study was undertaken to investigate how E-cadherin expression in human pancreatic adenocarcinoma and pancreatic cancer cell lines is regulated. METHODS: In 25 human pancreatic cancer resection specimens, the coding region of the E-cadherin gene (CDH1) was sequenced for somatic mutations. The tumour samples and 11 established human pancreatic cancer cell lines were analysed by immunohistochemistry, western blot analysis, chromatin immunoprecipitation and methylation-specific PCR. The role of specific histone deacetylase inhibitors (HDACi) on pancreatic tumour cell migration and proliferation was studied in vitro. RESULTS: Neither somatic mutations nor CDH1 promoter hypermethylation were found to be responsible for downregulation of E-cadherin in pancreatic cancer. In the transcriptionally active CDH1 promoter, acetylation of histones H3 and H4 was detected whereas HDAC1 and HDAC2 were found attached only to a silent promoter. Expression of ZEB1, a transcription factor known to recruit HDACs, was seen in E-cadherin-deficient cell lines in which ZEB1/HDAC complexes were found attached to the CDH1 promoter. Moreover, knockdown of ZEB1 prevented HDAC from binding to the CDH1 promoter, resulting in histone acetylation and expression of E-cadherin. HDACi treatment attenuated tumour cell migration and proliferation. CONCLUSIONS: These findings imply an important role for histone deacetylation in the downregulation of E-cadherin in human pancreatic cancer. Recruitment of HDACs to the CDH1 promoter is regulated by the transcription factor ZEB1, and inhibition of HDACs may be a promising antitumour therapy for pancreatic cancer.

16 Article A syngeneic orthotopic murine model of pancreatic adenocarcinoma in the C57/BL6 mouse using the Panc02 and 6606PDA cell lines. 2011

Partecke, L I / Sendler, M / Kaeding, A / Weiss, F U / Mayerle, J / Dummer, A / Nguyen, T D / Albers, N / Speerforck, S / Lerch, M M / Heidecke, C D / von Bernstorff, W / Stier, A. ·Department of General, Visceral, Thoracic and Vascular Surgery, Ernst Moritz Arndt University, Greifswald, Germany. ·Eur Surg Res · Pubmed #21720167.

ABSTRACT: BACKGROUND/AIMS: To develop a clinically relevant immunocompetent murine model to study pancreatic cancer using two different syngeneic pancreatic cancer cell lines and to assess MRI for its applicability in this model. METHODS: Two cell lines, 6606PDA and Panc02, were employed for the experiments. Cell proliferation and migration were monitored in vitro. Matrigel™ was tested for its role in tumor induction. Tumor cell growth was assessed after orthotopic injection of tumor cells into the pancreatic head of C57/BL6 mice by MRI and histology. RESULTS: Proliferation and migration of Panc02 were significantly faster than those of 6606PDA. Matrigel did not affect tumor growth/migration but prevented tumor cell spread after injection thus avoiding undesired peritoneal tumor growth. MRI could reliably monitor longitudinal tumor growth in both cell lines: Panc02 had a more irregular finger-like growth, and 6606PDA grew more spherically. Both tumors showed local invasiveness. Histologically, Panc02 showed a sarcoma-like undifferentiated growth pattern, whereas 6606PDA displayed a moderately differentiated glandular tumor growth. Panc02 mice had a significantly shorter (28 days) survival than 6606PDA mice (50 days). CONCLUSION: This model closely mimics human pancreatic cancer. MRI was invaluable for longitudinal monitoring of tumor growth thus reducing the number of mice required. Employing two different cell lines, this model can be used for various treatment and imaging studies.

17 Article Drug efflux transporter multidrug resistance-associated protein 5 affects sensitivity of pancreatic cancer cell lines to the nucleoside anticancer drug 5-fluorouracil. 2011

Nambaru, Praveen K / Hübner, Tobias / Köck, Kathleen / Mews, Steffen / Grube, Markus / Payen, Léa / Guitton, Jérôme / Sendler, Matthias / Jedlitschky, Gabriele / Rimmbach, Christian / Rosskopf, Dieter / Kowalczyk, Dariusz W / Kroemer, Heyo K / Weiss, Frank U / Mayerle, Julia / Lerch, Markus M / Ritter, Christoph A. ·Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt-University, Greifswald, Germany. ·Drug Metab Dispos · Pubmed #20930123.

ABSTRACT: Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 μM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU.

18 Article The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. 2010

Grocock, Christopher J / Rebours, Vinciane / Delhaye, Myriam N / Andrén-Sandberg, Ake / Weiss, Frank Ulrich / Mountford, Roger / Harcus, Matthew J / Niemczyck, Edyta / Vitone, Louis J / Dodd, Susanna / Jørgensen, Maiken Thyregod / Ammann, Rudolf W / Schaffalitzky de Muckadell, Ove / Butler, Jane V / Burgess, Phillip / Kerr, Bronwyn / Charnley, Richard / Sutton, Robert / Raraty, Michael G / Devière, Jacques / Whitcomb, David C / Neoptolemos, John P / Lévy, Philippe / Lerch, Markus M / Greenhalf, William / Anonymous3230644. ·School of Cancer Studies, University of Liverpool, UCD Building, Daulby Street, Liverpool, UK. ·Gut · Pubmed #19951905.

ABSTRACT: OBJECTIVE: To characterise the phenotypes associated with the p.A16V mutation of PRSS1. DESIGN: Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. PATIENTS: Participants were recruited on the basis of either family history of pancreatitis (acute or chronic) or the results of genetic testing. Families were categorised as having hereditary pancreatitis (HP), idiopathic disease or pancreatitis in a single generation. HP was defined as >or=2 cases in >or=2 generations. Main outcome measures Onset of painful episodes of pancreatitis, death from pancreatic cancer, diagnosis of diabetes mellitus and exocrine pancreatic failure. RESULTS: Ten families with p.A16V mutations were identified (22 affected individuals): six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI 5 to 25). There were eight confirmed cases of exocrine failure, four of whom also had diabetes mellitus. There were three pancreatic cancer cases. Two of these were confirmed as p.A16V carriers, only one of whom was affected by pancreatitis. Those with p.A16V pancreatitis were compared to affected individuals with p.R122H, p.N29I and no PRSS1 mutation. No significant differences were proven using logrank or Mann-Whitney U tests. CONCLUSIONS: Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.

19 Article Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. 2009

Weiss, Frank Ulrich / Marques, Ines J / Woltering, Joost M / Vlecken, Danielle H / Aghdassi, Ali / Partecke, Lars Ivo / Heidecke, Claus-Dieter / Lerch, Markus M / Bagowski, Christoph P. ·Universitätsklinikum Greifswald, Klinik für Innere Medizin A, Greifswald, Germany. ·Gastroenterology · Pubmed #19747919.

ABSTRACT: BACKGROUND & AIMS: The infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely owing to a high frequency of early metastasis. We identified microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumor cells and investigated the upstream and downstream regulatory mechanisms of miR-10a. METHODS: Northern blot analysis revealed increased expression levels of miR-10a in metastatic pancreatic adenocarcinoma. The role of miR-10a was analyzed by Morpholino and short interfering RNA transfection of pancreatic carcinoma cell lines and resected specimens of human pancreatic carcinoma. Metastatic behavior of primary pancreatic tumors and cancer cell lines was tested in xenotransplantation experiments in zebrafish embryos. RESULTS: We show that miR-10a expression promotes metastatic behavior of pancreatic tumor cells and that repression of miR-10a is sufficient to inhibit invasion and metastasis formation. We further show that miR-10a is a retinoid acid target and that retinoic acid receptor antagonists effectively repress miR-10a expression and completely block metastasis. This antimetastatic activity can be prevented by specific knockdown of HOX genes, HOXB1 and HOXB3. Interestingly, suppression of HOXB1 and HOXB3 in pancreatic cancer cells is sufficient to promote metastasis formation. CONCLUSIONS: These findings suggest that miR-10a is a key mediator of metastatic behavior in pancreatic cancer, which regulates metastasis via suppression of HOXB1 and HOXB3. Inhibition of miR-10a expression (with retinoic acid receptor antagonists) or function (with specific inhibitors) is a promising starting point for antimetastatic therapies.

20 Article Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model. 2009

Marques, Ines J / Weiss, Frank Ulrich / Vlecken, Danielle H / Nitsche, Claudia / Bakkers, Jeroen / Lagendijk, Anne K / Partecke, Lars Ivo / Heidecke, Claus-Dieter / Lerch, Markus M / Bagowski, Christoph P. ·Institute of Biology, Department of Integrative Zoology, University of Leiden, 2333 AL, Leiden, The Netherlands. i.j.marques@biology.leidenuniv.nl ·BMC Cancer · Pubmed #19400945.

ABSTRACT: BACKGROUND: Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. METHODS: We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. RESULTS: In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. CONCLUSION: Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen.