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Pancreatic Neoplasms: HELP
Articles by Hana Algül
Based on 23 articles published since 2009
(Why 23 articles?)
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Between 2009 and 2019, H. Algül wrote the following 23 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. 2017

Ruess, Dietrich A / Görgülü, Kivanc / Wörmann, Sonja M / Algül, Hana. ·Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. dietrich.ruess@uniklinik-freiburg.de. · Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. · Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. hana.alguel@mri.tum.de. ·Drugs Aging · Pubmed #28349415.

ABSTRACT: Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.

2 Review Stromal biology and therapy in pancreatic cancer: a changing paradigm. 2015

Neesse, Albrecht / Algül, Hana / Tuveson, David A / Gress, Thomas M. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Cold Spring Harbor Laboratory, Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA. · Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps-University, Marburg, Germany. ·Gut · Pubmed #25994217.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.

3 Review Interleukin-6 in inflammatory and malignant diseases of the pancreas. 2014

Lesina, Marina / Wörmann, Sonja Maria / Neuhöfer, Patrick / Song, Liang / Algül, Hana. ·II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaniger Strasse 22, Munich 81675, Germany. · II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaniger Strasse 22, Munich 81675, Germany. Electronic address: hana.alguel@lrz.tum.de. ·Semin Immunol · Pubmed #24572992.

ABSTRACT: Interleukin-6 is an important pro-inflammatory cytokine strongly linked to the most burdened exocrine pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer. However, its role in all these diseases is versatile and not completely defined. Several studies provided accumulating evidence that IL-6 is mainly involved in the JAK/STAT pathway activation promoting acute and chronic pancreatitis disease aggravation as well as pancreatic cancer initiation and progression. This review will focus on recent studies illustrating the role of IL-6 in acute and chronic pancreatitis and pancreatic oncogenesis. Further, a short overview of indicated disease pathologies will be given and the impact of IL-6 in JAK/STAT pathway, persistent STAT3 activation and cancer immunotherapy will be discussed.

4 Review The immune network in pancreatic cancer development and progression. 2014

Wörmann, S M / Diakopoulos, K N / Lesina, M / Algül, H. ·Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ·Oncogene · Pubmed #23851493.

ABSTRACT: The presence of stromal desmoplasia is a hallmark of spontaneous pancreatic ductal adenocarcinoma, forming a unique microenvironment that comprises many cell types. Only recently, the immune system has entered the pathophysiology of pancreatic ductal adenocarcinoma development. Tumor cells in the pancreas seem to dysbalance the immune system, thus facilitating spontaneous cancer development. This review will try to assemble all relevant data to demonstrate the implications of the immune network on spontaneous cancer development.

5 Clinical Trial Maintenance Olaparib for Germline 2019

Golan, Talia / Hammel, Pascal / Reni, Michele / Van Cutsem, Eric / Macarulla, Teresa / Hall, Michael J / Park, Joon-Oh / Hochhauser, Daniel / Arnold, Dirk / Oh, Do-Youn / Reinacher-Schick, Anke / Tortora, Giampaolo / Algül, Hana / O'Reilly, Eileen M / McGuinness, David / Cui, Karen Y / Schlienger, Katia / Locker, Gershon Y / Kindler, Hedy L. ·From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.) · Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.) · IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy · University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.) · Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.) · Fox Chase Cancer Center, Philadelphia (M.J.H.) · Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea · University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom · Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany · Memorial Sloan Kettering Cancer Center, New York (E.M.O.) · AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.) · Merck, Kenilworth, NJ (K.S.) · and the University of Chicago, Chicago (H.L.K.). ·N Engl J Med · Pubmed #31157963.

ABSTRACT: BACKGROUND: Patients with a germline METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline

6 Article Levels of the Autophagy-Related 5 Protein Affect Progression and Metastasis of Pancreatic Tumors in Mice. 2019

Görgülü, Kivanc / Diakopoulos, Kalliope N / Ai, Jiaoyu / Schoeps, Benjamin / Kabacaoglu, Derya / Karpathaki, Angeliki-Faidra / Ciecielski, Katrin J / Kaya-Aksoy, Ezgi / Ruess, Dietrich A / Berninger, Alexandra / Kowalska, Marlena / Stevanovic, Marija / Wörmann, Sonja M / Wartmann, Thomas / Zhao, Yue / Halangk, Walter / Voronina, Svetlana / Tepikin, Alexey / Schlitter, Anna Melissa / Steiger, Katja / Artati, Anna / Adamski, Jerzy / Aichler, Michaela / Walch, Axel / Jastroch, Martin / Hartleben, Götz / Mantzoros, Christos S / Weichert, Wilko / Schmid, Roland M / Herzig, Stephan / Krüger, Achim / Sainz, Bruno / Lesina, Marina / Algül, Hana. ·Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany; Comparative Experimental Pathology, Institute of Pathology, Technische Universität München, Munich, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany; Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany. · Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany. · Helmholtz Diabetes Center and German Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany. · Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts. · Department of Biochemistry, School of Medicine, Autónoma University of Madrid, Madrid, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: marina.lesina@tum.de. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de. ·Gastroenterology · Pubmed #30296435.

ABSTRACT: BACKGROUND AND AIMS: Cells in pancreatic ductal adenocarcinoma (PDAC) undergo autophagy, but its effects vary with tumor stage and genetic factors. We investigated the consequences of varying levels of the autophagy related 5 (Atg5) protein on pancreatic tumor formation and progression. METHODS: We generated mice that express oncogenic Kras in primary pancreatic cancer cells and have homozygous disruption of Atg5 (A5;Kras) or heterozygous disruption of Atg5 (A5 RESULTS: A5 CONCLUSIONS: In mice that express oncogenic Kras in pancreatic cells, heterozygous disruption of Atg5 and reduced protein levels promotes tumor development, whereas homozygous disruption of Atg5 blocks tumorigenesis. Therapeutic strategies to alter autophagy in PDAC should consider the effects of ATG5 levels to avoid the expansion of resistant and highly aggressive cells.

7 Article CD36-triggered cell invasion and persistent tissue colonization by tumor microvesicles during metastasis. 2019

Pfeiler, Susanne / Thakur, Manovriti / Grünauer, Petra / Megens, Remco T A / Joshi, Urjita / Coletti, Raffaele / Samara, Verena / Müller-Stoy, Geraldine / Ishikawa-Ankerhold, Hellen / Stark, Konstantin / Klingl, Andreas / Fröhlich, Thomas / Arnold, Georg J / Wörmann, Sonja / Bruns, Christiane J / Algül, Hana / Weber, Christian / Massberg, Steffen / Engelmann, Bernd. ·Institut für Laboratoriumsmedizin, Klinikum der Universität München, Ludwig Maximilians Universität, Munich, Germany. · Prophylaxe der Kreislaufkrankheiten, Ludwig Maximilians Universität, Munich, Germany. · Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. · Medizinische Klinik I, Ludwig Maximilians Universität, Munich, Germany. · Biologie I-Botanik, Ludwig Maximilians Universität, Munich, Germany. · Genzentrum, Ludwig Maximilians Universität, Munich, Germany. · Klinik und Poliklinik für Innere Medizin II, Technische Universität München, Munich, Germany. · Chirurgische Klinik, Universität zu Köln, Cologne, Germany. ·FASEB J · Pubmed #30207797.

ABSTRACT: Tumor microvesicles are a peculiar type of extracellular vesicles that circulate in the blood of patients with metastatic cancer. The itineraries and immune cell interactions of tumor microvesicles during the intravascular and extravascular stages of metastasis are largely unknown. We found that the lipid receptor CD36 is a major mediator of the engulfment of pancreatic tumor microvesicles by myeloid immune cells in vitro and critically samples circulating tumor microvesicles by resident liver macrophages in mice in vivo. Direct nanoscopic imaging of individual tumor microvesicles shows that the microvesicles rapidly decay during engulfment whereby their cargo is targeted concomitantly to the plasma membrane and the cytoplasm excluding lysosomal compartments. CD36 also promotes internalization of blood cell (nontumor) microvesicles, which involves endolysosomal pathways. A portion of tumor microvesicles circulating in the liver microcirculation traverses the vessel wall in a CD36-dependent way. Extravasated microvesicles colonize distinct perivascular Ly6C

8 Article Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. 2018

Ettrich, Thomas J / Berger, Andreas W / Perkhofer, Lukas / Daum, Severin / König, Alexander / Dickhut, Andreas / Wittel, Uwe / Wille, Kai / Geissler, Michael / Algül, Hana / Gallmeier, Eike / Atzpodien, Jens / Kornmann, Marko / Muche, Rainer / Prasnikar, Nicole / Tannapfel, Andrea / Reinacher-Schick, Anke / Uhl, Waldemar / Seufferlein, Thomas. ·Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. · Department of Oncology/Hematology, Fulda Hospital, Pacelliallee 4, 36043, Fulda, Germany. · Department of General and Visceral Surgery, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. · Department of Hematology and medical oncology, Johannes-Wesling-Klinikum Minden, Hans-Nolte-Straße 1, 32429, Minden, Germany. · Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Esslingen Hospital, Hirschlandstr. 97, 73730 Esslingen, Esslingen, Germany. · Department of Internal Medicine II, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. · Department of Gastroenterology and Endocrinology, University of Marburg, Baldingerstraße, 35043, Marburg, Germany. · Department of Medical Oncology and Hematology, Niels-Stensen-Kliniken, Alte Rothenfelder Str. 23, 49124, Georgsmarienhütte, Germany. · Department of General and Visceral Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Institute of Epidemiology and Medical Biometry, University of Ulm, Schwabstrasse 13, 89081, Ulm, Germany. · Department of Oncologie, Asklepios Klinik Barmbek, Rübenkamp 220, 22291, Hamburg, Germany. · Department of Pathology, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. · Department of Internal Medicine, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Surgery, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. thomas.seufferlein@uniklinik-ulm.de. ·BMC Cancer · Pubmed #30594153.

ABSTRACT: BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

9 Article Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. 2018

Ruess, Dietrich A / Heynen, Guus J / Ciecielski, Katrin J / Ai, Jiaoyu / Berninger, Alexandra / Kabacaoglu, Derya / Görgülü, Kivanc / Dantes, Zahra / Wörmann, Sonja M / Diakopoulos, Kalliope N / Karpathaki, Angeliki F / Kowalska, Marlena / Kaya-Aksoy, Ezgi / Song, Liang / van der Laan, Eveline A Zeeuw / López-Alberca, María P / Nazaré, Marc / Reichert, Maximilian / Saur, Dieter / Erkan, Mert M / Hopt, Ulrich T / Sainz, Bruno / Birchmeier, Walter / Schmid, Roland M / Lesina, Marina / Algül, Hana. ·Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. · Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany. · Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany. · Koç University School of Medicine, Istanbul, Turkey. · Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols", Madrid, Spain. · Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hana.alguel@mri.tum.de. ·Nat Med · Pubmed #29808009.

ABSTRACT: The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors

10 Article Distinct Pathogenesis of Pancreatic Cancer Microvesicle-Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo. 2018

Stark, Konstantin / Schubert, Irene / Joshi, Urjita / Kilani, Badr / Hoseinpour, Parandis / Thakur, Manovriti / Grünauer, Petra / Pfeiler, Susanne / Schmidergall, Tobias / Stockhausen, Sven / Bäumer, Markus / Chandraratne, Sue / von Brühl, Marie-Luise / Lorenz, Michael / Coletti, Raffaele / Reese, Sven / Laitinen, Iina / Wörmann, Sonja Maria / Algül, Hana / Bruns, Christiane J / Ware, Jerry / Mackman, Nigel / Engelmann, Bernd / Massberg, Steffen. ·From the Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany (K.S., I.S., B.K., P.H., T.S., S.S., S.C., M.-L.v.B., M.L., R.C., S.M.) · German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany (K.S., S.M.) · Institut für Laboratoriumsmedizin (U.J., M.T., P.G., S.P., M.B., B.E.) and Lehrstuhl für Anatomie, Histologie und Embryologie, Department of Veterinary Medicine (S.R.), Ludwig-Maximilians-Universität, Munich, Germany · Nuklearmedizinische Klinik und Poliklinik (I.L.) and II. Medizinische Klinik und Poliklinik (S.M.W., H.A.), Klinikum rechts der Isar, Technische Universität München, Munich, Germany · Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Universitätsklinik Köln, Cologne, Germany (C.J.B.) · Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock (J.W.) · and Department of Medicine, University of North Carolina at Chapel Hill (N.M.). ·Arterioscler Thromb Vasc Biol · Pubmed #29419408.

ABSTRACT: OBJECTIVE: Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT. APPROACH AND RESULTS: Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor-derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis. CONCLUSIONS: Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell-promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications.

11 Article ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. 2017

Perkhofer, Lukas / Schmitt, Anna / Romero Carrasco, Maria Carolina / Ihle, Michaela / Hampp, Stephanie / Ruess, Dietrich Alexander / Hessmann, Elisabeth / Russell, Ronan / Lechel, André / Azoitei, Ninel / Lin, Qiong / Liebau, Stefan / Hohwieler, Meike / Bohnenberger, Hanibal / Lesina, Marina / Algül, Hana / Gieldon, Laura / Schröck, Evelin / Gaedcke, Jochen / Wagner, Martin / Wiesmüller, Lisa / Sipos, Bence / Seufferlein, Thomas / Reinhardt, Hans Christian / Frappart, Pierre-Olivier / Kleger, Alexander. ·Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany. · Department of Internal Medicine, Division I, Hematology/Oncology, Clinical and Molecular Oncology, University Hospital Cologne, Cologne, Germany. · Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany. · Klinik und Poliklinik für Innere Medizin II, Technische Universitaet Muenchen, Munich, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Diabetes Centre, Department of Medicine, University of California at San Francisco, San Francisco, California. · Medical Faculty, Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany. · Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany. · Department of Pathology, University Medical Center Goettingen, Goettingen, Germany. · Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Department of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany. alexander.kleger@uni-ulm.de pierre.olivier.frappart@uni-ulm.de. ·Cancer Res · Pubmed #28790064.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional

12 Article Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells. 2017

Demir, Ihsan Ekin / Kujundzic, Kristina / Pfitzinger, Paulo L / Saricaoglu, Ömer Cemil / Teller, Steffen / Kehl, Timo / Reyes, Carmen Mota / Ertl, Linda S / Miao, Zhenhua / Schall, Thomas J / Tieftrunk, Elke / Haller, Bernhard / Diakopoulos, Kalliope Nina / Kurkowski, Magdalena U / Lesina, Marina / Krüger, Achim / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; ekin.demir@tum.de gueralp.ceyhan@tum.de. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · ChemoCentryx, Inc., Mountain View, CA 94043. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Institute for Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. ·Proc Natl Acad Sci U S A · Pubmed #27986950.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.

13 Article RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis. 2016

Lesina, Marina / Wörmann, Sonja Maria / Morton, Jennifer / Diakopoulos, Kalliope Nina / Korneeva, Olga / Wimmer, Margit / Einwächter, Henrik / Sperveslage, Jan / Demir, Ihsan Ekin / Kehl, Timo / Saur, Dieter / Sipos, Bence / Heikenwälder, Mathias / Steiner, Jörg Manfred / Wang, Timothy Cragin / Sansom, Owen J / Schmid, Roland Michael / Algül, Hana. · ·J Clin Invest · Pubmed #27454298.

ABSTRACT: Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.

14 Article Loss of P53 Function Activates JAK2-STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated With Patient Survival. 2016

Wörmann, Sonja M / Song, Liang / Ai, Jiaoyu / Diakopoulos, Kalliope N / Kurkowski, Magdalena U / Görgülü, Kivanc / Ruess, Dietrich / Campbell, Andrew / Doglioni, Claudio / Jodrell, Duncan / Neesse, Albrecht / Demir, Ihsan E / Karpathaki, Angelica-Phaedra / Barenboim, Maxim / Hagemann, Thorsten / Rose-John, Stefan / Sansom, Owen / Schmid, Roland M / Protti, Maria P / Lesina, Marina / Algül, Hana. ·II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Beatson Institute for Cancer Research, University of Glasgow, Glasgow, United Kingdom. · Pathology Unit, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy. · Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom. · Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University, Marburg, Germany. · Chirurgische Klinik und Poliklinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. · Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, United Kingdom. · Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany. · Tumor Immunology Unit, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de. ·Gastroenterology · Pubmed #27003603.

ABSTRACT: BACKGROUND & AIMS: One treatment strategy for pancreatic ductal adenocarcinoma is to modify, rather than deplete, the tumor stroma. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) is associated with progression of pancreatic and other solid tumors. We investigated whether loss of P53 function contributes to persistent activation of STAT3 and modification of the pancreatic tumor stroma in patients and mice. METHODS: Stat3, Il6st (encodes gp130), or Trp53 were disrupted, or a mutant form of P53 (P53R172H) or transgenic sgp130 were expressed, in mice that developed pancreatic tumors resulting from expression of activated KRAS (KrasG12D, KC mice). Pancreata were collected and analyzed by immunohistochemistry, in situ hybridization, quantitative reverse-transcription polymerase chain reaction (qPCR), or immunoblot assays; fluorescence-activated cell sorting was performed to identify immune cells. We obtained frozen pancreatic tumor specimens from patients and measured levels of phosphorylated STAT3 and P53 by immunohistochemistry; protein levels were associated with survival using Kaplan-Meier analyses. We measured levels of STAT3, P53, ligands for gp130, interleukin 6, cytokines, sonic hedgehog signaling, STAT3 phosphorylation (activation), and accumulation of reactive oxygen species in primary pancreatic cells from mice. Mice with pancreatic tumors were given gemcitabine and a Janus kinase 2 (JAK2) inhibitor; tumor growth was monitored by 3-dimensional ultrasound. RESULTS: STAT3 was phosphorylated constitutively in pancreatic tumor cells from KC mice with loss or mutation of P53. Tumor cells of these mice accumulated reactive oxygen species and had lower activity of the phosphatase SHP2 and prolonged phosphorylation of JAK2 compared with tumors from KC mice with functional P53. These processes did not require the gp130 receptor. Genetic disruption of Stat3 in mice, or pharmacologic inhibitors of JAK2 or STAT3 activation, reduced fibrosis and the numbers of pancreatic stellate cells in the tumor stroma and altered the types of immune cells that infiltrated tumors. Mice given a combination of gemcitabine and a JAK2 inhibitor formed smaller tumors and survived longer than mice given control agents; the tumor stroma had fewer activated pancreatic stellate cells, lower levels of periostin, and alterations in collagen production and organization. Phosphorylation of STAT3 correlated with P53 mutation and features of infiltrating immune cells in human pancreatic tumors. Patients whose tumors had lower levels of phosphorylated STAT3 and functional P53 had significantly longer survival times than patients with high levels of phosphorylated STAT3 and P53 mutation. CONCLUSIONS: In pancreatic tumors of mice, loss of P53 function activates JAK2-STAT3 signaling, which promotes modification of the tumor stroma and tumor growth and resistance to gemcitabine. In human pancreatic tumors, STAT3 phosphorylation correlated with P53 mutation and patient survival time. Inhibitors of this pathway slow tumor growth and stroma formation, alter immune cell infiltration, and prolong survival of mice. Transcript profiling: ArrayExpress accession number: E-MTAB-3278.

15 Article Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients. 2016

De Monte, Lucia / Wörmann, Sonja / Brunetto, Emanuela / Heltai, Silvia / Magliacane, Gilda / Reni, Michele / Paganoni, Anna Maria / Recalde, Helios / Mondino, Anna / Falconi, Massimo / Aleotti, Francesca / Balzano, Gianpaolo / Algül, Hana / Doglioni, Claudio / Protti, Maria Pia. ·Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. San Raffaele Vita-Salute University, Milan, Italy. · Pathology Unit, IRCCS, San Raffaele Hospital, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Medical Oncology Department, IRCCS, San Raffaele Hospital, Milan, Italy. · Laboratory for Modeling and Scientific Computing (MOX), Dipartimento di Matematica, Politecnico di Milano, Milan, Italy. · Hematology, Ospedale San Matteo, Pavia, Italy. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Lymphocyte Activation Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · San Raffaele Vita-Salute University, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Pancreatic Surgery Unit, IRCCS, San Raffaele Hospital, Milan, Italy. · Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Pancreatic Surgery Unit, IRCCS, San Raffaele Hospital, Milan, Italy. · San Raffaele Vita-Salute University, Milan, Italy. Pathology Unit, IRCCS, San Raffaele Hospital, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. m.protti@hsr.it. ·Cancer Res · Pubmed #26873846.

ABSTRACT: In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell-derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer. Cancer Res; 76(7); 1792-803. ©2016 AACR.

16 Article Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. 2016

Demir, Ihsan Ekin / Tieftrunk, Elke / Schorn, Stephan / Saricaoglu, Ömer Cemil / Pfitzinger, Paulo L / Teller, Steffen / Wang, Kun / Waldbaur, Christine / Kurkowski, Magdalena U / Wörmann, Sonja Maria / Shaw, Victoria E / Kehl, Timo / Laschinger, Melanie / Costello, Eithne / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Hepatic, Biliary & Pancreatic Surgery, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK. · Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK Liverpool NIHR Pancreas Biomedical Research Unit, Liverpool, UK. ·Gut · Pubmed #26762195.

ABSTRACT: OBJECTIVE: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN: Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS: Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS: Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression.

17 Article Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. 2014

Demir, Ihsan Ekin / Boldis, Alexandra / Pfitzinger, Paulo L / Teller, Steffen / Brunner, Eva / Klose, Natascha / Kehl, Timo / Maak, Matthias / Lesina, Marina / Laschinger, Melanie / Janssen, Klaus-Peter / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC) · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA). ·J Natl Cancer Inst · Pubmed #25106646.

ABSTRACT: BACKGROUND: In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer. METHODS: Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling. RESULTS: Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75(NTR)-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase. CONCLUSIONS: Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves-and not cancer cells-migrate first during NI.

18 Article Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. 2013

Demir, Ihsan Ekin / Schorn, Stephan / Schremmer-Danninger, Elisabeth / Wang, Kun / Kehl, Timo / Giese, Nathalia A / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ekin.demir@tum.de ·PLoS One · Pubmed #23555989.

ABSTRACT: BACKGROUND: Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown. METHODS: Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients. RESULTS: In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients. CONCLUSION: Pancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.

19 Article Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. 2013

Conradt, Laura / Henrich, Annika / Wirth, Matthias / Reichert, Maximilian / Lesina, Marina / Algül, Hana / Schmid, Roland M / Krämer, Oliver H / Saur, Dieter / Schneider, Günter. ·II. Medizinische Klinik, Technische Universität München, München, Germany. ·Int J Cancer · Pubmed #23115126.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFκB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC.

20 Article Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis. 2012

Hamidi, Tewfik / Algül, Hana / Cano, Carla Eliana / Sandi, Maria José / Molejon, Maria Inés / Riemann, Marc / Calvo, Ezequiel Luis / Lomberk, Gwen / Dagorn, Jean-Charles / Weih, Falk / Urrutia, Raul / Schmid, Roland Michael / Iovanna, Juan Lucio. ·Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. ·J Clin Invest · Pubmed #22565310.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.

21 Article In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging. 2011

Eser, Stefan / Messer, Marlena / Eser, Philipp / von Werder, Alexander / Seidler, Barbara / Bajbouj, Monther / Vogelmann, Roger / Meining, Alexander / von Burstin, Johannes / Algül, Hana / Pagel, Philipp / Schnieke, Angelika E / Esposito, Irene / Schmid, Roland M / Schneider, Günter / Saur, Dieter. ·II Medizinische Klinik, Technische Universität München, 81675 Munich, Germany. ·Proc Natl Acad Sci U S A · Pubmed #21628592.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC.

22 Article Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. 2011

Lesina, Marina / Kurkowski, Magdalena U / Ludes, Katharina / Rose-John, Stefan / Treiber, Matthias / Klöppel, Günter / Yoshimura, Akihiko / Reindl, Wolfgang / Sipos, Bence / Akira, Shizuo / Schmid, Roland M / Algül, Hana. ·II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ·Cancer Cell · Pubmed #21481788.

ABSTRACT: Physiological levels of Kras(G12D) are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras(G12D), IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development.

23 Article [74-year-old patient with cystic pancreatic lesions. An endoscopy-based algorithm]. 2011

Wörmann, S / Meining, A / Hartel, M / Ludwig, L / Prinz, C / Gaa, J / Schulz, S / Schmid, R M / Algül, H. ·II. medizinische Klinik, Ambulanz für Pankreaserkrankungen, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany. ·Internist (Berl) · Pubmed #20941475.

ABSTRACT: Often, equivocal pancreatic cystic masses in a patient cannot be clearly identified. We report on a 74-year-old patient who consulted us with size-gaining multi-cystic lesions located at the pancreatic head and tail as well as with an increased CA 19-9 level. By using diagnostic methods as ultrasound, radiological images and innovative endoscopic techniques an intraductal papillary mucinous neoplasm (IPMN) was diagnosed. Evaluation of equivocal cystic lesions requires developing of further strategies as well as integration of new concepts: We present a diagnostic algorithm based on endoscopy that enables us to perform an adapted therapy by having a more accurate evaluation and the opportunity to gain samples where unclear lesions are given.