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Pancreatic Neoplasms: HELP
Articles by Ole Helm
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Ole Helm wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. 2014

Helm, Ole / Mennrich, Ruben / Petrick, Domantas / Goebel, Lisa / Freitag-Wolf, Sandra / Röder, Christian / Kalthoff, Holger / Röcken, Christoph / Sipos, Bence / Kabelitz, Dieter / Schäfer, Heiner / Oberg, Hans-Heinrich / Wesch, Daniela / Sebens, Susanne. ·Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UKSH Campus Kiel, Kiel, Germany. · Institute of Immunology, UKSH Campus Kiel, Kiel, Germany. · Institute of Medical Informatics and Statistics, UKSH Campus Kiel, Kiel, Germany. · Institute of Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany. · Institute of Pathology, UKSH Campus Kiel, Kiel, Germany. · Institute of Pathology; University Tübingen, Tübingen, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH Campus Kiel, Kiel, Germany. ·PLoS One · Pubmed #24797069.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP.

2 Article Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells. 2019

Rahn, Sascha / Barbosa, Philippe Dänzer / Möller, Julia Luisa / Ammar, Nourhane / Demetrowitsch, Tobias / Helm, Ole / Wesch, Daniela / Sipos, Bence / Röcken, Christoph / Schwarz, Karin / Schäfer, Heiner / Sebens, Susanne. ·Institute for Experimental Cancer Research, University of Kiel and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany. · Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany. · Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany. · Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany. · Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany. · Institute for Human Nutrition & Food Science, Department of Food Technology, University of Kiel, 24118 Kiel, Germany. · Institute of Immunology, University of Kiel and UKSH Campus Kiel, 24105 Kiel, Germany. · BAG für Pathologie und Molekularpathologie Stuttgart, 70176 Stuttgart, Germany. · Department of Pathology, UKSH Campus Kiel, 24105 Kiel, Germany. ·Cancers (Basel) · Pubmed #31877753.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is amongst the most fatal malignancies and its development is highly associated with inflammatory processes such as chronic pancreatitis (CP). Since the succinate dehydrogenase subunit B (SDHB) is regarded as tumor suppressor that is lost during cancer development, this study investigated the impact of M1-macrophages as part of the inflammatory microenvironment on the expression as well as function of SDHB in benign and premalignant pancreatic ductal epithelial cells (PDECs). Immunohistochemical analyses on pancreatic tissue sections from CP patients and control individuals revealed a stronger SDHB expression in ducts of CP tissues being associated with a greater abundance of macrophages compared to ducts in control tissues. Accordingly, indirect co-culture with M1-macrophages led to clearly elevated SDHB expression and SDH activity in benign H6c7-pBp and premalignant H6c7-kras PDECs. While siRNA-mediated SDHB knockdown in these cells did not affect glucose and lactate uptake after co-culture, SDHB knockdown significantly promoted PDEC growth which was associated with increased proliferation and decreased effector caspase activity particularly in co-cultured PDECs. Overall, these data indicate that SDHB expression and SDH activity are increased in PDECs when exposed to pro-inflammatory macrophages as a counterregulatory mechanism to prevent excessive PDEC growth triggered by the inflammatory environment.

3 Article POLE Score: a comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma. 2019

Rahn, Sascha / Krüger, Sandra / Mennrich, Ruben / Goebel, Lisa / Wesch, Daniela / Oberg, Hans-Heinrich / Vogel, Ilka / Ebsen, Michael / Röcken, Christoph / Helm, Ole / Sebens, Susanne. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UK-SH), Campus Kiel, Kiel, Germany. · Department of Pathology, CAU and UK-SH, Campus Kiel, Kiel, Germany. · Institute of Immunology, CAU and UK-SH, Campus Kiel, Kiel, Germany. · Department of Surgery, Community Hospital Kiel, Kiel, Germany. · Institute of Pathology, Community Hospital Kiel, Kiel, Germany. ·Oncotarget · Pubmed #30899426.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) being characterized by a pronounced stromal compartment is commonly diagnosed at an advanced stage limiting curative treatment options. Although therapeutical targeting of immune checkpoint regulators like programmed death 1 ligand 1 (PD-L1) represent a promising approach that substantially improved survival of several highly aggressive malignancies, convincing indicators for response prediction are still lacking for PDAC which might be attributed to the insufficient characterization of PD-L1 status. Therefore, we investigated PD-L1 expression by immunohistochemistry in a well characterized cohort of 59 PDAC and 18 peritumoral tissues. Despite the histopathological homogeneity within our cohort, tumor tissues exhibited a great heterogeneity regarding PD-L1 expression. Considering distinct PD-L1 expression patterns, we established the novel POLE Score that incorporates overall PD-L1 expression (P), cellular Origin of PD-L1 (O), PD-L1 level in tumor-associated Lymph follicles (L) and Enumerated local PD-L1 distribution (E). We show that tumoral PD-L1 expression is higher compared to peritumoral areas. Furthermore, POLE Score parameters correlated with overall survival, tumor grade, Ki67 status, local proximity of tumor cells and particular stroma composition. For the first time, we demonstrate that PD-L1 is mostly expressed by stroma and rarely by tumor cells in PDAC. Moreover, our

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

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

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

5 Article Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. 2018

Rahn, Sascha / Zimmermann, Vivien / Viol, Fabrice / Knaack, Hendrike / Stemmer, Kerstin / Peters, Lena / Lenk, Lennart / Ungefroren, Hendrik / Saur, Dieter / Schäfer, Heiner / Helm, Ole / Sebens, Susanne. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany. · Department of General Surgery and Thoracic Surgery, UKSH Campus Kiel, Germany; First Department of Medicine, UKSH Campus Lübeck, Lübeck, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. Electronic address: susanne.sebens@email.uni-kiel.de. ·Cancer Lett · Pubmed #29222037.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is associated with hyperglycemia and a risk to develop pancreatic ductal adenocarcinoma (PDAC), one of the most fatal malignancies. Cancer stem cells (CSC) are essential for initiation and maintenance of tumors, and acquisition of CSC-features is linked to epithelial-mesenchymal-transition (EMT). The present study investigated whether hyperglycemia promotes EMT and CSC-features in premalignant and malignant pancreatic ductal epithelial cells (PDEC). Under normoglycemia (5 mM d-glucose), Panc1 PDAC cells but not premalignant H6c7-kras cells exhibited a mesenchymal phenotype along with pronounced colony formation. While hyperglycemia (25 mM d-glucose) did not impact the mesenchymal phenotype of Panc1 cells, CSC-properties were aggravated exemplified by increased Nanog expression and Nanog-dependent formation of holo- and meroclones. In H6c7-kras cells, high glucose increased secretion of Transforming-Growth-Factor-beta1 (TGF-β1) as well as TGF-β1 signaling, and in a TGF-β1-dependent manner reduced E-cadherin expression, increased Nestin expression and number of meroclones. Finally, reduced E-cadherin expression was detected in pancreatic ducts of hyperglycemic but not normoglycemic mice. These data suggest that hyperglycemia promotes the acquisition of mesenchymal and CSC-properties in PDEC by activating TGF-β signaling and might explain how T2DM facilitates pancreatic tumorigenesis.

6 Article The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma. 2017

Lenk, Lennart / Pein, Maren / Will, Olga / Gomez, Beatriz / Viol, Fabrice / Hauser, Charlotte / Egberts, Jan-Hendrik / Gundlach, Jan-Paul / Helm, Ole / Tiwari, Sanjay / Weiskirchen, Ralf / Rose-John, Stefan / Röcken, Christoph / Mikulits, Wolfgang / Wenzel, Patrick / Schneider, Günter / Saur, Dieter / Schäfer, Heiner / Sebens, Susanne. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. · Cell Biology and Tumor Biology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany. · Molecular Imaging North Competence Center, Clinic of Radiology and Neuroradiology, CAU and UKSH Campus Kiel, Kiel, Germany. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, UKSH Campus Kiel, Kiel, Germany. · Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University, Aachen, Germany. · Department of Biochemistry, CAU, Kiel, Germany. · Institute of Pathology, UKSH Campus Kiel, Kiel, Germany. · Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. ·Oncoimmunology · Pubmed #29296518.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when liver metastases already emerged. This study elucidated the impact of hepatic stromal cells on growth behavior of premalignant and malignant pancreatic ductal epithelial cells (PDECs). Liver sections of tumor-bearing KPC mice comprised micrometastases displaying low proliferation located in an unobtrusive hepatic microenvironment whereas macrometastases containing more proliferating cells were surrounded by hepatic myofibroblasts (HMFs). In an age-related syngeneic PDAC mouse model livers with signs of age-related inflammation exhibited significantly more proliferating disseminated tumor cells (DTCs) and micrometastases despite comparable primary tumor growth and DTC numbers. Hepatic stellate cells (HSC), representing a physiologic liver stroma, promoted an IL-8 mediated quiescence-associated phenotype (QAP) of PDECs in coculture. QAP included flattened cell morphology, Ki67-negativity and reduced proliferation, elevated senescence-associated β galactosidase activity and diminished p-Erk/p-p38-ratio. In contrast, proliferation of PDECs was enhanced by VEGF in the presence of HMF. Switching the micromilieu from HSC to HMF or blocking VEGF reversed QAP in PDECs. This study demonstrates how HSCs induce and maintain a reversible QAP in disseminated PDAC cells, while inflammatory HMFs foster QAP reversal and metastatic outgrowth. Overall, the importance of the hepatic microenvironment in induction and reversal of dormancy during PDAC metastasis is emphasized.

7 Article Negative control of TRAIL-R1 signaling by transforming growth factor β1 in pancreatic tumor cells involves Smad-dependent down regulation of TRAIL-R1. 2016

Radke, David I / Ungefroren, Hendrik / Helm, Ole / Voigt, Susann / Alp, Gökhan / Braun, Hendrik / Hübner, Sebastian / Dilchert, Janine / Sebens, Susanne / Adam, Dieter / Kalthoff, Holger / Trauzold, Anna. ·Institute for Experimental Cancer Research, University of Kiel, D-24105 Kiel, Germany. · First Department of Medicine, UKSH and University of Lübeck, D-23538 Lübeck, Germany. · Institute of Immunology, University of Kiel, D-24105 Kiel, Germany. · Institute for Experimental Cancer Research, University of Kiel, D-24105 Kiel, Germany; Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, Germany. Electronic address: atrauzold@email.uni-kiel.de. ·Cell Signal · Pubmed #27492861.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by both, overexpression of transforming growth factor (TGF)β and resistance of the tumor cells to many apoptosis-inducing stimuli. The latter negatively impacts the outcome of therapeutic efforts and represents one important mechanism which tumor cells utilize to escape the immune surveillance. Since TGFβ acts as a tumor promoter in advanced tumor stages and suppression of apoptosis is a known driver of tumor progression, it is possible that TGFβ functions as a crucial determinant of tumor cell sensitivity to apoptosis in PDAC. Here, we have studied the impact of TGFβ on TNF-related apoptosis inducing ligand (TRAIL)-induced signaling in PDAC cells. In TGFβ-responsive Panc1 and Colo357 cells, TGFβ1 reduced total and plasma membrane-associated levels of TRAIL-R1 but not those of TRAIL-R2. Consistent with the known predominant role of TRAIL-R1 in TRAIL-mediated signaling in PDAC, TGFβ1 inhibited TRAIL-induced DISC formation and apoptosis as well as phosphorylation of MAPKs and IκBα. Similarly, it also reduced signaling of TRAIL-R1 following its specific activation with an agonistic antibody. In contrast, specific TRAIL-R2 signaling remained unchanged. The TGFβ1 effect on TRAIL-R1 expression was mimicked by ectopic expression of a kinase-active version of the TGFβ type I receptor ALK5 (ALK5-T204D) but not by ALK5 double mutant lacking the ability to phosphorylate Smad proteins (RImL45-T204D). Moreover, TGFβ regulation of TRAIL-R1 was absent in two PDAC cell lines lacking the Smad4 gene DPC4 and siRNA-mediated silencing of Smad4 in Smad4-positive Panc1 cells abolished the TGFβ-mediated decrease in TRAIL-R1 expression, together showing that ALK5/Smad4 signaling is crucial for TGFβ regulation of TRAIL-R1 expression. Our results suggest a novel tumor-promoting function of TGFβ1. By downregulating TRAIL-R1, TGFβ1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of PDAC.

8 Article The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1. 2016

Genrich, Geeske / Kruppa, Marcus / Lenk, Lennart / Helm, Ole / Broich, Anna / Freitag-Wolf, Sandra / Röcken, Christoph / Sipos, Bence / Schäfer, Heiner / Sebens, Susanne. ·Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. stu94401@mail.uni-kiel.de. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. marcus.kruppa@gmail.com. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. lennartlenk@email.uni-kiel.de. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. olehelm@email.uni-kiel.de. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. anna-k-broich@web.de. · Institute of Medical Informatics and Statistics, UKSH Campus Kiel, Brunswiker Str. 10, 24105, Kiel, Germany. freitag@medinfo.uni-kiel.de. · Department of Pathology, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 14, 24105, Kiel, Germany. Christoph.Roecken@uk-sh.de. · Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany. Bence.Sipos@med.uni-tuebingen.de. · Laboratory of Molecular Gastroenterology & Hepatology, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 6, 24105, Kiel, Germany. hschaef@1med.uni-kiel.de. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. susanne.sebens@email.uni-kiel.de. ·BMC Cancer · Pubmed #26915435.

ABSTRACT: BACKGROUND: Nuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible transcription factor being essential in regulating cell homeostasis. Thus, acute induction of Nrf2 in epithelial cells exposed to inflammation confers protection from oxidative cell damage and mutagenesis supporting an anti-tumorigenic role for Nrf2. However, pancreatic ductal adenocarcinoma (PDAC) is characterized by persistent Nrf2 activity conferring therapy resistance which points to a pro-tumorigenic role of Nrf2. A similar dichotomous role in tumorigenesis is described for the Transforming Growth Factor-beta 1 (TGF-β1). The present study therefore aimed at elucidating whether the switch of Nrf2 function towards a tumor promoting one relates to the modulation of TGF-β1 induced cell responses and whether this might occur early in PDAC development. METHODS: In situ analysis comprised immunohistochemical stainings of activated (phosphorylated) Nrf2 and Ki67 in pancreatic tissues containing normal ducts and pancreatic intraepithelial neoplasia (PanINs). In vitro, Nrf2 levels in benign (H6c7-pBp), premalignant (H6c7-kras) and malignant (Colo357) pancreatic ductal epithelial cells were modulated by Nrf2 specific siRNA or Nrf2 overexpression. Then, the effect of Nrf2 alone and in combination with TGF-β1 on cell growth and survival was investigated by cell counting, Ki67 staining and apoptosis assays. The underlying cell signaling was investigated by western blotting. Statistical analysis was performed by Shapiro-Wilk test for normal distribution. Parametric data were analyzed by one-way ANOVA, while non-parametric data were analyzed by Kruskal-Wallis one-way ANOVA on ranks. RESULTS: Significantly elevated expression of activated Nrf2 and Ki67 could be detected in PanINs but not in normal pancreatic ductal epithelium. While the effect of Nrf2 on basal cell growth of H6c7-pBp, H6c7-kras and Colo357 cells was minor, it clearly attenuated the growth inhibiting effects of TGF-β1 in all cell lines. This enhanced Nrf2-mediated cell survival was predominantly based on an enhanced proliferative activity. Accordingly, expression of p21 expression along with expression of phospho-p38 and phospho-Smad3 was diminished whereas Erk-phosphorylation was enhanced under these conditions. CONCLUSIONS: Overall, our data demonstrate that Nrf2 being elevated in early precursor lesions counteracts the growth inhibiting function of TGF-β1 already in benign and premalignant pancreatic ductal epithelial cells. This could represent one fundamental mechanism underlying the functional switch of both- TGF-β1 and Nrf2 - which may manifest already in early stages of PDAC development.

9 Article The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells. 2015

Arfmann-Knübel, Sarah / Struck, Birte / Genrich, Geeske / Helm, Ole / Sipos, Bence / Sebens, Susanne / Schäfer, Heiner. ·Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany. · Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany. · Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstraße 8, 72076, Tübingen, Germany. ·PLoS One · Pubmed #26226105.

ABSTRACT: Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.

10 Article CD4 2015

Goebel, Lisa / Grage-Griebenow, Evelin / Gorys, Artur / Helm, Ole / Genrich, Geeske / Lenk, Lennart / Wesch, Daniela / Ungefroren, Hendrik / Freitag-Wolf, Sandra / Sipos, Bence / Röcken, Christoph / Schäfer, Heiner / Sebens, Susanne. ·Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany. · Institute of Immunology; Christian-Albrechts-University and UKSH Campus Kiel ; Kiel, Germany. · First Department of Medicine; UKSH Campus Lübeck ; Lübeck, Germany. · Institute of Medical Informatics and Statistics; UKSH Campus Kiel ; Kiel, Germany. · Department of Pathology and Neuropathology; University Hospital Tübingen ; Tübingen, Germany. · Institute of Pathology; UKSH Campus Kiel ; Kiel, Germany. · Laboratory of Molecular Gastroenterology & Hepatology; Department of Internal Medicine I; UKSH Campus Kiel ; Kiel, Germany. ·Oncoimmunology · Pubmed #26137395.

ABSTRACT: Chronic pancreatitis (CP) is a risk factor of pancreatic ductal adenocarcinoma (PDAC) and characterized by a pronounced desmoplastic reaction with CD4

11 Article M1 and M2: there is no "good" and "bad"-How macrophages promote malignancy-associated features in tumorigenesis. 2014

Helm, Ole / Held-Feindt, Janka / Schäfer, Heiner / Sebens, Susanne. ·Group of Inflammatory Carcinogenesis; Institute for Experimental Medicine; UKSH ; Kiel, Germany. · Department of Neurosurgery; UKSH Campus Kiel ; Kiel, Germany. · Laboratory of Molecular Gastroenterology & Hepatology; Department of Internal Medicine I; UKSH Campus Kiel ; Kiel, Germany. ·Oncoimmunology · Pubmed #25610733.

ABSTRACT: We recently identified tumor-associated macrophages from pancreatic ductal adenocarcinoma sharing pro- and anti-inflammatory characteristics. Already in residence in the setting of chronic pancreatitis, local macrophages confer malignancy-associated features to premalignant pancreatic ductal epithelial cells by both promoting and inhibiting inflammation, either of which can foster malignant conversion. Our findings support the concept that contrasting modes of inflammation can promote tumorigenesis.

12 Article Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. 2014

Helm, Ole / Held-Feindt, Janka / Grage-Griebenow, Evelin / Reiling, Norbert / Ungefroren, Hendrik / Vogel, Ilka / Krüger, Uwe / Becker, Thomas / Ebsen, Michael / Röcken, Christoph / Kabelitz, Dieter / Schäfer, Heiner / Sebens, Susanne. ·Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UK S-H Campus, Kiel, Germany. ·Int J Cancer · Pubmed #24458546.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) still ranking 4th in the order of fatal tumor diseases is characterized by a profound tumor stroma with high numbers of tumor-associated macrophages (TAMs). Driven by environmental factors, monocytes differentiate into M1- or M2-macrophages, the latter commonly regarded as being protumorigenic. Because a detailed analysis of TAMs in human PDAC development is still lacking, freshly isolated PDAC-derived TAMs were analyzed for their phenotype and impact on epithelial-mesenchymal-transition (EMT) of benign (H6c7) and malignant (Colo357) pancreatic ductal epithelial cells. TAMs exhibited characteristics of M1-macrophages (expression of HLA-DR, IL-1β, or TNF-α) and M2-macrophages (expression of CD163 and IL-10). In the presence of TAMs, H6c7, and Colo357 cells showed an elongated cell shape along with an increased expression of mesenchymal markers such as vimentin and reduced expression of epithelial E-cadherin. Similar to TAMs, in vitro generated M1- and M2-macrophages both mediated EMT in H6c7 and Colo357 cells. M1-macrophages acquired M2-characteristics during coculture that could be prevented by GM-CSF treatment. However, M1-macrophages still potently induced EMT in H6c7 and Colo357 cells although lacking M2-characteristics. Overall, these data demonstrate that TAMs exhibit anti- as well as proinflammatory properties that equally contribute to EMT induction in PDAC initiation and development.

13 Article Rac1b negatively regulates TGF-β1-induced cell motility in pancreatic ductal epithelial cells by suppressing Smad signalling. 2014

Ungefroren, Hendrik / Sebens, Susanne / Giehl, Klaudia / Helm, Ole / Groth, Stephanie / Fändrich, Fred / Röcken, Christoph / Sipos, Bence / Lehnert, Hendrik / Gieseler, Frank. ·First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, Lübeck, Germany. ·Oncotarget · Pubmed #24378395.

ABSTRACT: Transforming growth factor (TGF)-β1 promotes progression of pancreatic ductal adenocarcinoma (PDAC) by enhancing epithelial-mesenchymal transition, cell migration/invasion, and metastasis, in part by cooperating with the small GTPase Rac1. Prompted by the observation of higher expression of Rac1b, an alternatively spliced Rac1 isoform, in pancreatic ductal epithelial cells and in patients with chronic pancreatitis vs. PDAC, as well as in long-time vs. short-time survivors among PDAC patients, we asked whether Rac1b might negatively affect TGF-β1 prometastatic function. Interestingly, the non-malignant pancreatic ductal epithelial cell line H6c7 exhibited a higher ratio of active Rac1b to total Rac1b than the TGF-β1-responsive PDAC cell lines Panc-1 and Colo357. Notably, siRNA-mediated silencing of Rac1b increased TGF-β1/Smad-dependent migratory activities in H6c7, Colo357, and Panc-1 cells, while ectopic overexpression of Rac1b in Panc-1 cells attenuated TGF-β1-induced cell motility. Depletion of Rac1b in Panc-1 cells enhanced TGF-β1/Smad-dependent expression of promoter-reporter genes and of the endogenous Slug gene. Moreover, Rac1b depletion resulted in a higher and more sustained C-terminal phosphorylation of Smad3 and Smad2, suggesting that Rac1b is involved in Smad2/3 dephosphorylation/inactivation. Since pharmacologic or siRNA-mediated inhibition of Smad3 but not Smad2 was able to alleviate the Rac1b siRNA effect on TGF-β1-induced cell migration, our results suggests that Rac1b inhibits TGF-β1-induced cell motility in pancreatic ductal epithelial cells by blocking the function of Smad3. Moreover, Rac1b may act as an endogenous inhibitor of Rac1 in TGF-β1-mediated migration and possibly metastasis. Hence, it could be exploited for diagnostic/prognostic purposes or even therapeutically in late-stage PDAC as an antimetastatic agent.