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Pancreatic Neoplasms: HELP
Articles by Matthias Sendler
Based on 13 articles published since 2009
(Why 13 articles?)
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Between 2009 and 2019, M. Sendler wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 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.

2 Article Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges. 2017

Maertin, Sandrina / Elperin, Jason M / Lotshaw, Ethan / Sendler, Matthias / Speakman, Steven D / Takakura, Kazuki / Reicher, Benjamin M / Mareninova, Olga A / Grippo, Paul J / Mayerle, Julia / Lerch, Markus M / Gukovskaya, Anna S. ·Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. · Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California. · Department of Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany. · Department of Medicine, University of Illinois-Chicago, Chicago, Illinois; and. · Department of Medicine II, University Hospital, Ludwig-Maximilian-University, Munich, Germany. · Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; agukovsk@ucla.edu. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #28705806.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC.

3 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.

4 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.

5 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.

6 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.

7 Article TRAIL Promotes Tumor Growth in a Syngeneic Murine Orthotopic Pancreatic Cancer Model and Affects the Host Immune Response. 2016

Beyer, Katharina / Normann, Lars / Sendler, Matthias / Käding, Andre / Heidecke, Claus-Dieter / Partecke, Lars Ivo / von Bernstorff, Wolfram. ·From the *Departments of General, Visceral, Thoracic and Vascular Surgery and †Medicine A (Gastroenterology and Nephrology), University Medicine Greifswald, Ernst-Moritz-Arndt-University, Greifswald, Germany. ·Pancreas · Pubmed #26390425.

ABSTRACT: OBJECTIVES: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is currently being evaluated as a possible biological agent for cancer treatment. However, many tumor cells are resistant to TRAIL-induced apoptosis. In these cases, TRAIL may activate different pathways promoting tumor growth as well as showing different interactions with the immunological tumor microenvironment. In this study, the impact of TRAIL on tumor growth and survival in a syngeneic model of TRAIL-resistant pancreatic cancer cells was investigated. METHODS: Murine 6606PDA pancreatic cancer cells were injected into the pancreatic heads of TRAIL mice and their littermates. To examine a direct effect of TRAIL on tumor cells, cultures of 6606PDA were TRAIL stimulated. RESULTS: The TRAIL mice displayed significantly decreased tumor volumes and an enhanced overall survival in pancreatic cancer. The decreased tumor growth in TRAIL mice was accompanied by a decrease of regulatory CD4 cells within tumors. Concordantly, TRAIL treatment of wild-type mice enhanced tumor growth and increased the fraction of regulatory CD4 cells. Yet, a direct effect of TRAIL on 6606PDA cells was not detected. CONCLUSIONS: Thus, TRAIL can promote tumor growth in TRAIL-resistant tumor cells. This may restrict possible future clinical applications of TRAIL in pancreatic cancer.

8 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.

9 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.

10 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.

11 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.

12 Article In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model. 2011

Partecke, Ivo L / Kaeding, André / Sendler, Matthias / Albers, Nele / Kühn, Jens-P / Speerforck, Sven / Roese, Sebastian / Seubert, Florian / Diedrich, Stephan / Kuehn, Sandra / Weiss, Ulrich F / Mayerle, Julia / Lerch, Markus M / Hadlich, Stefan / Hosten, Norbert / Heidecke, Claus-D / Puls, Ralf / von Bernstorff, Wolfram. ·Department of General, Visceral, Thoracic and Vascular Surgery, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Str. 23 b, Greifswald, Germany. ·BMC Cancer · Pubmed #21276229.

ABSTRACT: BACKGROUND: Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability. METHODS: 6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA. RESULTS: MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/-22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals. CONCLUSIONS: This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.

13 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.