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Pancreatic Neoplasms: HELP
Articles by Holger Kalthoff
Based on 30 articles published since 2009
(Why 30 articles?)
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Between 2009 and 2019, H. Kalthoff wrote the following 30 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Emerging therapeutic targets and agents for pancreatic cancer therapy--where are we and where we have to go? 2011

Sebens, Susanne / Kalthoff, Holger. · ·Anticancer Agents Med Chem · Pubmed #21492077.

ABSTRACT: -- No abstract --

2 Review Interleukin-6: a villain in the drama of pancreatic cancer development and progression. 2014

Holmer, Reinhild / Goumas, Freya A / Waetzig, Georg H / Rose-John, Stefan / Kalthoff, Holger. ·Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, D-24105 Kiel, Germany. hkalthoff@email.uni-kiel.de. ·Hepatobiliary Pancreat Dis Int · Pubmed #25100121.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6 (IL-6), which plays an important role in a wide range of biologic activities. DATA SOURCES: A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6, inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed. RESULTS: IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras, mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions. CONCLUSION: IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target.

3 Review The diversity between pancreatic head and body/tail cancers: clinical parameters and in vitro models. 2013

Ling, Qi / Xu, Xiao / Zheng, Shu-Sen / Kalthoff, Holger. ·Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, 310003, China. zyzss@zju.edu.cn. ·Hepatobiliary Pancreat Dis Int · Pubmed #24103277.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) can be divided into head, body and tail cancers according to the anatomy. Distinctions in tissue composition, vascularization and innervations have been clearly identified between the head and body/tail of the pancreas both in embryological development and in histopathology. To understand the postulated genotype difference, we present comprehensive information on two PDAC cell lines as typical representatives originating from pancreatic head and body/tail cancers, respectively. DATA SOURCE: In the present review, we compare the difference between pancreatic head and body/tail cancers regarding clinical parameters and introducing an in vitro model. RESULTS: Increasing evidence has shown that tumors at different locations (head vs body/tail) display different clinical presentation (e.g. incidence, symptom), treatment efficiency (e.g. surgery, chemotherapy) and thus patient prognosis. However, the genetic or molecular diversity (e.g. mutations, microRNA) between the two subtypes of PDAC has not been elucidated so far. They present different chemo- and/or radio-resistance, extracellular matrix adhesion and invasiveness, as well as genetic profiles. CONCLUSION: Genetic and tumor biological diversity exists in PDAC according to the tumor localization.

4 Review Impact of death receptor signaling on the malignancy of pancreatic ductal adenocarcinoma. 2011

Röder, Christian / Trauzold, Anna / Kalthoff, Holger. ·Sektion für Molekulare Onkologie, Institut für Experimentelle Tumorforschung, Krebszentrum Nord - CCC, Universitätsklinikum Schleswig-Holstein, Campus Kiel, 24105 Kiel, Arnold-Heller-Str. 3, Haus 18, Germany. ·Eur J Cell Biol · Pubmed #21129814.

ABSTRACT: Pancreatic ductal adenocarcinoma, PDAC, is a type of tumor with late diagnosis, rapid progression and poor prognosis. It is mostly unresponsive to chemo- and radiation therapy due to a marked resistance against apoptosis induction via both the intrinsic and extrinsic pathway. Accordingly, also activation of death receptors of the TNF-receptor superfamily does not or hardly induces apoptosis in PDAC cells. The reasons for this resistance include expression of multiple inhibitory proteins that block apoptotic signaling at almost every step of the signaling cascade. Moreover and more importantly, death receptors such as CD95/Fas, TRAIL-R1/-R2 and TNF-R1 exhibit marked non-apoptotic functions after ligand binding leading to strong proinflammatory responses, which contribute to survival, proliferation, migration and invasion, causing an even more pronounced malignant phenotype. This non-apoptotic signal transduction is facilitated via distinct adapter proteins, such as TRAF2 that bind to death receptor complexes and stimulate proinflammatory signal pathways leading to activation of NF-κB and AP-1 transcription factors. Therapeutic interventions in oncology utilizing death ligands, e.g. TRAIL, or triggering death receptors indirectly, must be carefully evaluated with respect to possible "side effects" and should be designed in a way counteracting non-apoptotic proinflammatory signaling.

5 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.

6 Article Cytoplasmic TRAIL-R1 is a positive prognostic marker in PDAC. 2018

Gundlach, Jan-Paul / Hauser, Charlotte / Schlegel, Franka Maria / Böger, Christine / Röder, Christian / Röcken, Christoph / Becker, Thomas / Egberts, Jan-Hendrik / Kalthoff, Holger / Trauzold, Anna. ·Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, Haus 18, 24105, Kiel, Germany. · Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller Str. 3 (Haus 17), D-24105, Kiel, Germany. · Department of Pathology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, Haus 14, 24105, Kiel, Germany. · Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, Haus 18, 24105, Kiel, Germany. atrauzold@email.uni-kiel.de. · Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller Str. 3 (Haus 17), D-24105, Kiel, Germany. atrauzold@email.uni-kiel.de. ·BMC Cancer · Pubmed #30064384.

ABSTRACT: BACKGROUND: The death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, also in the case of pancreatic ductal adenocarcinoma (PDAC). In their canonical localization at the plasma membrane, TRAIL-R1/-R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Although, they have repeatedly been found intracellular, in the cytoplasm and in the nucleus, their functions in intracellular locations are still not well understood. Likewise, studies dealing with the prognostic relevance of TRAIL-Rs located in particular cellular compartments are very rare. For PDAC, the correlation of nuclear TRAIL-R2 with worse patients' prognosis has been shown recently. Corresponding data on TRAIL-R1 are not available so far. METHODS: In the present study we analyzed the expression of TRAIL-R1 in 106 PDACs and 28 adjacent, peritumoral non-malignant pancreatic ducts with special emphasis on its cytoplasmic and nuclear localization and correlated the immunohistochemical findings with clinico-pathological patient characteristics. RESULTS: TRAIL-R1 was found in 93.4% of all PDAC samples. Cytoplasmic staining was present with very similar intensity in tumor and normal tissue. In contrast, nuclear TRAIL-R1 staining was significantly stronger in tumor compared to normal tissue (p = 0.006). Interestingly, we found that the number of cells with cytoplasmic TRAIL-R1 staining negatively correlates with tumor grading (p = 0.043). No such correlation could be detected for nuclear TRAIL-R1. Neither, cytoplasmic nor nuclear TRAIL-R1 staining showed a correlation with other clinico-pathological parameter such as pTNM categories. However, Kaplan-Meier analyses revealed significantly prolonged median survival of patients with positive cytoplasmic TRAIL-R1 expression in more than 80% of tumor cells compared to patients with tumors containing a smaller quantity of cells positively stained for cytoplasmic TRAIL-R1 (20 vs. 8 months; p = 0.004). CONCLUSION: Cytoplasmic TRAIL-R1 is a positive prognostic marker for patients with PDAC. Our findings indicate that loss of cytoplasmic TRAIL-R1 results in recurrent disease with more malignant phenotype thus suggesting anti-tumor activities of cytoplasmic TRAIL-R1 in PDAC.

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

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

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

8 Article Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo. 2017

Leanza, Luigi / Romio, Matteo / Becker, Katrin Anne / Azzolini, Michele / Trentin, Livio / Managò, Antonella / Venturini, Elisa / Zaccagnino, Angela / Mattarei, Andrea / Carraretto, Luca / Urbani, Andrea / Kadow, Stephanie / Biasutto, Lucia / Martini, Veronica / Severin, Filippo / Peruzzo, Roberta / Trimarco, Valentina / Egberts, Jan-Hendrik / Hauser, Charlotte / Visentin, Andrea / Semenzato, Gianpietro / Kalthoff, Holger / Zoratti, Mario / Gulbins, Erich / Paradisi, Cristina / Szabo, Ildiko. ·Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy. · Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy. · Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. · Department of Biomedical Sciences, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy. · Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy. · Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Arnold-Heller-Strasse 3 (Haus 17), 24105 Kiel, Germany. · Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA. Electronic address: erich.gulbins@uni-due.de. · Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy. Electronic address: cristina.paradisi@unipd.it. · Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy. Electronic address: ildi@civ.bio.unipd.it. ·Cancer Cell · Pubmed #28399409.

ABSTRACT: The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.

9 Article The prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma. 2017

Ling, Qi / Xu, Xiao / Ye, Panpan / Xie, Haiyang / Gao, Feng / Hu, Qichao / Liu, Zhikun / Wei, Xuyong / Röder, Christian / Trauzold, Anna / Kalthoff, Holger / Zheng, Shusen. ·Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. · Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China. · The Ophthalmology Center, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. · Institute for Experimental Cancer Research, Comprehensive Cancer Center North, CAU, Kiel, Germany. ·Oncotarget · Pubmed #28122349.

ABSTRACT: Different clinical presentations and prognoses have been implied between pancreatic head and body/tail cancers. We aimed to identify the prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). Thirty-two pairs of patients with strictly matched early stage (II) pancreatic head and body/tail cancers were enrolled. The molecular feature of the two subtypes of PDAC was assessed on the level of miRNA expression. Out of the 64 patients, 34 (53.1%) had tumor recurrence after radical resection during the follow-up period (2.3 ± 0.8 years). Both overall and tumor-free survival were significantly higher in the patients with pancreatic body/tail cancer compared with those with pancreatic head cancer. Patient age and tumor location were the independent prognostic factors for tumor recurrence. A remarkably lower expression of miR-501-3p and higher expression of miR-375 were found and were further verified in pancreatic body/tail cancer tissues compared with pancreatic head cancer tissues. The low expression of miR-501-3p was significantly associated with a low risk of tumor recurrence. Both, subcutaneous and orthotopic PDAC mouse models presented highly invasive tumor phenotypes upon up-regulated miR-501-3p expression. An in vitro study showed that miR-501-3p promoted the invasiveness of PDAC cells possibly via suppressing E-cadherin. In summary, at resectable early stage, pancreatic body/tail cancer presents a less malignant phenotype associated with deregulation of miR-501-3p compared with pancreatic head cancer.

10 Article Ion channels in control of pancreatic stellate cell migration. 2017

Storck, Hannah / Hild, Benedikt / Schimmelpfennig, Sandra / Sargin, Sarah / Nielsen, Nikolaj / Zaccagnino, Angela / Budde, Thomas / Novak, Ivana / Kalthoff, Holger / Schwab, Albrecht. ·Institut für Physiologie II, 48149 Münster, Gemany. · UKSH, Campus Kiel, Institut für Experimentelle Tumorforschung (IET), Sektion Molekulare Onkologie, D-24105 Kiel, Germany. · Institut für Physiologie I, 48149 Münster, Gemany. · Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK 2100 Copenhagen, Denmark. ·Oncotarget · Pubmed #27903970.

ABSTRACT: Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all "hallmarks of cancer" such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of KCa3.1 channels in PSCs. KCa3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of KCa3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of KCa3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2+ concentration ([Ca2+]i). KCa3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca2+]i and calpain activity. KCa3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of KCa3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology.

11 Article Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma. 2017

Zaccagnino, Angela / Managò, Antonella / Leanza, Luigi / Gontarewitz, Artur / Linder, Bernhard / Azzolini, Michele / Biasutto, Lucia / Zoratti, Mario / Peruzzo, Roberta / Legler, Karen / Trauzold, Anna / Kalthoff, Holger / Szabo, Ildiko. ·Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany. · Department of Biology, University of Padova, viale G. Colombo 3. Padova, I-35121 Italy. · Department of Biomedical Sciences, University of Padova, I-35121 Italy. · CNR Institute of Neuroscience, Padova, Italy. ·Oncotarget · Pubmed #27542263.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the µM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.

12 Article In silico analysis of the transportome in human pancreatic ductal adenocarcinoma. 2016

Zaccagnino, A / Pilarsky, C / Tawfik, D / Sebens, S / Trauzold, A / Novak, I / Schwab, A / Kalthoff, H. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. angela.zacca@email.uni-kiel.de. · Department of Surgery, University Clinic, Krankenhausstr. 12, 91054, Erlangen, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. · Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark. · Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, 48149, Muenster, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. holger.kalthoff@email.uni-kiel.de. ·Eur Biophys J · Pubmed #27652669.

ABSTRACT: The altered expression and/or activity of ion channels and transporters (transportome) have been associated with malignant behavior of cancer cells and were proposed to be a hallmark of cancer. However, the impact of altered transportome in epithelial cancers, such as pancreatic ductal adenocarcinoma (PDAC), as well as its pathophysiological consequences, still remains unclear. Here, we report the in silico analysis of 840 transportome genes in PDAC patients' tissues. Our study was focused on the transportome changes and their correlation with functional and behavioral responses in PDAC tumor and stromal compartments. The dysregulated gene expression datasets were filtered using a cut-off of fold-change values ≤-2 or ≥2 (adjusted p value ≤0.05). The dysregulated transportome genes were clearly associated with impaired physiological secretory mechanisms and/or pH regulation, control of cell volume, and cell polarity. Additionally, some down-regulated transportome genes were found to be closely linked to epithelial cell differentiation. Furthermore, the observed decrease in genes coding for calcium and chloride transport might be a mechanism for evasion of apoptosis. In conclusion, the current work provides a comprehensive overview of the altered transportome expression and its association with predicted PDAC malignancy with special focus on the epithelial compartment.

13 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.

14 Article Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells. 2015

Geisen, Ulf / Zenthoefer, Marion / Peipp, Matthias / Kerber, Jannik / Plenge, Johannes / Managò, Antonella / Fuhrmann, Markus / Geyer, Roland / Hennig, Steffen / Adam, Dieter / Piker, Levent / Rimbach, Gerald / Kalthoff, Holger. ·Division of Molecular Oncology, Institute for Experimental Cancer Research, Medical Faculty, CAU, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. ugeisen@email.uni-kiel.de. · CRM, Coastal Research & Management, 24159 Kiel, Germany. m.zenthoefer@web.de. · Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. m.peipp@med2.uni-kiel.de. · Division of Molecular Oncology, Institute for Experimental Cancer Research, Medical Faculty, CAU, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. jannik-kerber@t-online.de. · Institute of Immunology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. Johannes.plenge@gmx.de. · Department of Biology, University of Padua, 35131 Padua, Italy. manago.antonella@gmail.com. · Numares AG, 93053 Regensburg, Germany. markus.fuhrmann@numares.com. · Numares AG, 93053 Regensburg, Germany. Roland.Geyer@numares.com. · CRM, Coastal Research & Management, 24159 Kiel, Germany. steffen.hennig@crm-online.de. · Institute of Immunology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. dadam@email.uni-kiel.de. · CRM, Coastal Research & Management, 24159 Kiel, Germany. lpiker@oceanbasis.de. · Institute of Human Nutrition and Food Science, Christian-Albrechts University of Kiel, 24118 Kiel, Germany. rimbach@foodsci.uni-kiel.de. · Division of Molecular Oncology, Institute for Experimental Cancer Research, Medical Faculty, CAU, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. hkalthoff@email.uni-kiel.de. ·Mar Drugs · Pubmed #26204945.

ABSTRACT: Pancreatic cancer is one of the most aggressive cancer entities, with an extremely poor 5-year survival rate. Therefore, novel therapeutic agents with specific modes of action are urgently needed. Marine organisms represent a promising source to identify new pharmacologically active substances. Secondary metabolites derived from marine algae are of particular interest. The present work describes cellular and molecular mechanisms induced by an HPLC-fractionated, hydrophilic extract derived from the Baltic brown seaweed Fucus vesiculosus (Fv1). Treatment with Fv1 resulted in a strong inhibition of viability in various pancreatic cancer cell lines. This extract inhibited the cell cycle of proliferating cells due to the up-regulation of cell cycle inhibitors, shown on the mRNA (microarray data) and protein level. As a result, cells were dying in a caspase-independent manner. Experiments with non-dividing cells showed that proliferation is a prerequisite for the effectiveness of Fv1. Importantly, Fv1 showed low cytotoxic activity against non-malignant resting T cells and terminally differentiated cells like erythrocytes. Interestingly, accelerated killing effects were observed in combination with inhibitors of autophagy. Our in vitro data suggest that Fv1 may represent a promising new agent that deserves further development towards clinical application.

15 Article Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. 2015

von Karstedt, Silvia / Conti, Annalisa / Nobis, Max / Montinaro, Antonella / Hartwig, Torsten / Lemke, Johannes / Legler, Karen / Annewanter, Franka / Campbell, Andrew D / Taraborrelli, Lucia / Grosse-Wilde, Anne / Coy, Johannes F / El-Bahrawy, Mona A / Bergmann, Frank / Koschny, Ronald / Werner, Jens / Ganten, Tom M / Schweiger, Thomas / Hoetzenecker, Konrad / Kenessey, Istvan / Hegedüs, Balazs / Bergmann, Michael / Hauser, Charlotte / Egberts, Jan-Hendrik / Becker, Thomas / Röcken, Christoph / Kalthoff, Holger / Trauzold, Anna / Anderson, Kurt I / Sansom, Owen J / Walczak, Henning. ·Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. · Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK; Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. · Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany. · German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA. · German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany. · Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK. · Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany. · Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. · Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. · Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. · 2nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary. · Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary. · Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. · Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. · Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany; Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. · Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk. ·Cancer Cell · Pubmed #25843002.

ABSTRACT: Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.

16 Article A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy. 2015

Cardone, Rosa Angela / Greco, Maria Raffaella / Zeeberg, Katrine / Zaccagnino, Angela / Saccomano, Mara / Bellizzi, Antonia / Bruns, Philipp / Menga, Marta / Pilarsky, Christian / Schwab, Albrecht / Alves, Frauke / Kalthoff, Holger / Casavola, Valeria / Reshkin, Stephan Joel. ·Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy. · Institute for Experimental Cancer Research, Christian Albrechts University, Arnold-Heller-Str. 7, D-24105, Kiel, Germany. · Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, D-37075, Gottingen, Germany. · Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, D-48149, Muenster, Germany. · University Hospital Carl Gustav Carus, Technical University of Dresden, TU Dresden, Fetscherstraße 74, D-01307, Dresden, Germany. · Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy. · Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy. Electronic address: stephanjoel.reshkin@uniba.it. ·Neoplasia · Pubmed #25748234.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.

17 Article Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. 2015

Goumas, Freya A / Holmer, Reinhild / Egberts, Jan-Hendrik / Gontarewicz, Artur / Heneweer, Carola / Geisen, Ulf / Hauser, Charlotte / Mende, Maria-Margarete / Legler, Karen / Röcken, Christoph / Becker, Thomas / Waetzig, Georg H / Rose-John, Stefan / Kalthoff, Holger. ·Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, Germany. · Clinic for Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany. · CONARIS Research Institute AG, Kiel, Germany. · Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany. ·Int J Cancer · Pubmed #25604508.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human tumors, with radical surgical resection as the only curative treatment option. However, resection is only possible in a small fraction of patients, and about 80% of the patients develop recurrencies. PDAC development is facilitated by the cytokine interleukin-6 (IL-6), which acts via classic and trans-signaling. Both pathways are inhibited by the anti-IL-6-receptor antibody tocilizumab, whereas the fusion protein sgp130Fc specifically blocks trans-signaling. Here, we show that conservative or adjuvant therapy with both inhibitors reduces tumor growth in an orthotopic model of human Colo357 cells in SCID/bg mice. In the conservative setting, median primary tumor weight was reduced 2.4-fold for tocilizumab and 4.4-fold for sgp130Fc. sgp130Fc additionally led to a decrease in microvessel density, which was not observed with tocilizumab. In the adjuvant therapeutic setting after surgical resection of the primary tumor, treatment with tocilizumab or sgp130Fc decreased the local recurrence rate from 87.5% in the control group to 62.5 or 50%, respectively. Furthermore, the median weight of the local recurrent tumors was clearly diminished, and both inhibitors reduced the number of distant metastases. A significant reduction of tumor weight and metastases-comparable to gemcitabine treatment-was also observed with both inhibitors in another model using the poorly differentiated PancTuI cells. Our findings demonstrate the inhibition of IL-6 as a new treatment option in PDAC.

18 Article Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. 2015

Madhavan, Bindhu / Yue, Shijing / Galli, Uwe / Rana, Sanyukta / Gross, Wolfgang / Müller, Miryam / Giese, Nathalia A / Kalthoff, Holger / Becker, Thomas / Büchler, Markus W / Zöller, Margot. ·Tumor Cell Biology, General Surgery, University of Heidelberg, Heidelberg, Germany. ·Int J Cancer · Pubmed #25388097.

ABSTRACT: Late diagnosis contributes to pancreatic cancer (PaCa) dismal prognosis, urging for reliable, early detection. Serum-exosome protein and/or miRNA markers might be suitable candidates, which we controlled for patients with PaCa. Protein markers were selected according to expression in exosomes of PaCa cell line culture supernatants, but not healthy donors' serum-exosomes. miRNA was selected according to abundant recovery in microarrays of patients with PaCa, but not healthy donors' serum-exosomes and exosome-depleted serum. According to these preselections, serum-exosomes were tested by flow cytometry for the PaCa-initiating cell (PaCIC) markers CD44v6, Tspan8, EpCAM, MET and CD104. Serum-exosomes and exosome-depleted serum was tested for miR-1246, miR-4644, miR-3976 and miR-4306 recovery by qRT-PCR. The majority (95%) of patients with PaCa (131) and patients with nonPa-malignancies reacted with a panel of anti-CD44v6, -Tspan8, -EpCAM and -CD104. Serum-exosomes of healthy donors' and patients with nonmalignant diseases were not reactive. Recovery was tumor grading and staging independent including early stages. The selected miR-1246, miR-4644, miR-3976 and miR-4306 were significantly upregulated in 83% of PaCa serum-exosomes, but rarely in control groups. These miRNA were also elevated in exosome-depleted serum of patients with PaCa, but at a low level. Concomitant evaluation of PaCIC and miRNA serum-exosome marker panels significantly improved sensitivity (1.00, CI: 0.95-1) with a specificity of 0.80 (CI: 0.67-0.90) for PaCa versus all others groups and of 0.93 (CI: 0.81-0.98) excluding nonPa-malignancies. Thus, the concomitant evaluation of PaCIC and PaCa-related miRNA marker panels awaits retrospective analyses of larger cohorts, as it should allow for a highly sensitive, minimally-invasive PaCa diagnostics.

19 Article Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells. 2014

Haselmann, Verena / Kurz, Alexandra / Bertsch, Uwe / Hübner, Sebastian / Olempska-Müller, Monika / Fritsch, Jürgen / Häsler, Robert / Pickl, Andreas / Fritsche, Hendrik / Annewanter, Franka / Engler, Christine / Fleig, Barbara / Bernt, Alexander / Röder, Christian / Schmidt, Hendrik / Gelhaus, Christoph / Hauser, Charlotte / Egberts, Jan-Hendrik / Heneweer, Carola / Rohde, Anna Maria / Böger, Christine / Knippschild, Uwe / Röcken, Christoph / Adam, Dieter / Walczak, Henning / Schütze, Stefan / Janssen, Ottmar / Wulczyn, F Gregory / Wajant, Harald / Kalthoff, Holger / Trauzold, Anna. ·Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany. · Institute of Immunology, University of Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany. · Zoological Institute, University of Kiel, Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany; Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University of Kiel, Kiel, Germany. · Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University of Kiel, Kiel, Germany. · Clinic for Diagnostic Radiology, University of Kiel, Kiel, Germany. · Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pathology, University of Kiel, Kiel, Germany. · Department of General, Visceral and Transplantation Surgery, Centre of Surgery, University of Ulm, Ulm, Germany. · Centre for Cell Death, Cancer and Inflammation, University College London Cancer Institute, London, United Kingdom. · Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany. Electronic address: atrauzold@email.uni-kiel.de. ·Gastroenterology · Pubmed #24120475.

ABSTRACT: BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL-R1) (TNFRSF10A) and TRAIL-R2 (TNFRSF10B) on the plasma membrane bind ligands that activate apoptotic and other signaling pathways. Cancer cells also might have TRAIL-R2 in the cytoplasm or nucleus, although little is known about its activities in these locations. We investigated the functions of nuclear TRAIL-R2 in cancer cell lines. METHODS: Proteins that interact with TRAIL-R2 initially were identified in pancreatic cancer cells by immunoprecipitation, mass spectrometry, and immunofluorescence analyses. Findings were validated in colon, renal, lung, and breast cancer cells. Functions of TRAIL-R2 were determined from small interfering RNA knockdown, real-time polymerase chain reaction, Drosha-activity, microRNA array, proliferation, differentiation, and immunoblot experiments. We assessed the effects of TRAIL-R2 overexpression or knockdown in human pancreatic ductal adenocarcinoma (PDAC) cells and their ability to form tumors in mice. We also analyzed levels of TRAIL-R2 in sections of PDACs and non-neoplastic peritumoral ducts from patients. RESULTS: TRAIL-R2 was found to interact with the core microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45, and NF90 in nuclei of PDAC and other tumor cells. Knockdown of TRAIL-R2 increased Drosha-mediated processing of the let-7 microRNA precursor primary let-7 (resulting in increased levels of mature let-7), reduced levels of the let-7 targets (LIN28B and HMGA2), and inhibited cell proliferation. PDAC tissues from patients had higher levels of nuclear TRAIL-R2 than non-neoplastic pancreatic tissue, which correlated with increased nuclear levels of HMGA2 and poor outcomes. Knockdown of TRAIL-R2 in PDAC cells slowed their growth as orthotopic tumors in mice. Reduced nuclear levels of TRAIL-R2 in cultured pancreatic epithelial cells promoted their differentiation. CONCLUSIONS: Nuclear TRAIL-R2 inhibits maturation of the microRNA let-7 in pancreatic cancer cell lines and increases their proliferation. Pancreatic tumor samples have increased levels of nuclear TRAIL-R2, which correlate with poor outcome of patients. These findings indicate that in the nucleus, death receptors can function as tumor promoters and might be therapeutic targets.

20 Article Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. 2014

Unruh, Dusten / Turner, Kevin / Srinivasan, Ramprasad / Kocatürk, Begüm / Qi, Xiaoyang / Chu, Zhengtao / Aronow, Bruce J / Plas, David R / Gallo, Catherine A / Kalthoff, Holger / Kirchhofer, Daniel / Ruf, Wolfram / Ahmad, Syed A / Lucas, Fred V / Versteeg, Henri H / Bogdanov, Vladimir Y. ·Division of Hematology/Oncology, Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH. ·Int J Cancer · Pubmed #23754313.

ABSTRACT: Alternatively spliced tissue factor (asTF) promotes neovascularization and monocyte recruitment via integrin ligation. While asTF mRNA has been detected in some pancreatic ductal adenocarcinoma (PDAC) cell lines and increased asTF expression can promote PDAC growth in a subcutaneous model, the expression of asTF protein in bona fide PDAC lesions and/or its role in metastatic spread are yet to be ascertained. We here report that asTF protein is abundant in lesional and stromal compartments of the five studied types of carcinoma including PDAC. Analysis of 29 specimens of PDAC revealed detectable asTF in >90% of the lesions with a range of staining intensities. asTF levels in PDAC lesions positively correlated with the degree of monocyte infiltration. In an orthotopic model, asTF-overexpressing high-grade PDAC cell line Pt45P1/asTF+ produced metastases to distal lymph nodes, which stained positive for asTF. PDAC cells stimulated with and/or overexpressing asTF exhibited upregulation of genes implicated in PDAC progression and metastatic spread. Pt45P1/asTF+ cells displayed higher coagulant activity compared to Pt45P1 cells; the same effect was observed for cell-derived microparticles (MPs). Our findings demonstrate that asTF is expressed in PDAC and lymph node metastases and potentiates PDAC spread in vivo. asTF elicits global changes in gene expression likely involved in tumor progression and metastatic dissemination, and it also enhances the procoagulant potential of PDAC cells and cell-derived MPs. Thus, asTF may comprise a novel therapeutic target to treat PDAC and, possibly, its thrombotic complications.

21 Article Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma. 2013

Lehnen, Nils C / von Mässenhausen, Anne / Kalthoff, Holger / Zhou, Hui / Glowka, Tim / Schütte, Ute / Höller, Tobias / Riesner, Katarina / Boehm, Diana / Merkelbach-Bruse, Sabine / Kirfel, Jutta / Perner, Sven / Gütgemann, Ines. ·Institute of Pathology, University Hospital of Bonn, Bonn, Germany. ·Histopathology · Pubmed #23808822.

ABSTRACT: AIMS: Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro. METHODS AND RESULTS: Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398. CONCLUSIONS: FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs.

22 Article Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the "a disintegrin and metalloproteases" 10 and 17. 2013

Chitadze, Guranda / Lettau, Marcus / Bhat, Jaydeep / Wesch, Daniela / Steinle, Alexander / Fürst, Daniel / Mytilineos, Joannis / Kalthoff, Holger / Janssen, Ottmar / Oberg, Hans-Heinrich / Kabelitz, Dieter. ·Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany. ·Int J Cancer · Pubmed #23526433.

ABSTRACT: The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Thus, the presence of MICA/B on transformed cells contributes to tumor immunosurveillance. Consequently, the proteolytic cleavage of MICA/B is regarded as an important immune escape mechanism of various cancer cells. To investigate the molecular machinery responsible for the shedding of endogenous MICA/B, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. We demonstrate that the "a disintegrin and metalloproteases" (ADAMs) 10 and 17 are largely responsible for the generation of soluble MICA/B. Pharmacological inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. Moreover, we report that in the prostate carcinoma cell line PC-3, MICA was not shed at all but rather was secreted in exosomes. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.

23 Article TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells. 2013

Zhou, Dong-Hui / Yang, Li-Na / Roder, Christian / Kalthoff, Holger / Trauzold, Anna. ·Department of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. zdh19838@hotmail.com ·Hepatobiliary Pancreat Dis Int · Pubmed #23392805.

ABSTRACT: BACKGROUND: The death ligand, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), induces apoptosis and non-apoptotic signaling in some tumor cells. The purpose of this study was to investigate the roles of the pro-apoptotic TRAIL receptors, TRAIL-R1 and TRAIL-R2, as well as Bcl-xL and TRAF2 in TRAIL-induced expression of the pro-inflammatory cytokine IL-8 and the invasion-promoting protein urokinase (uPA) in pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: Colo357wt, Colo357/TRAF2, Colo357/Bcl-xL, Panc89 and PancTuI cells were stimulated with TRAIL and uPA and IL-8 expression was detected using real-time PCR. Antagonistic, receptor-specific antibodies were used to investigate the effects of TRAIL-R1 or TRAIL-R2 inhibition. RESULTS: Dose-dependent increases in uPA and IL-8 expression were detected following TRAIL stimulation in PDAC cells. These effects were inhibited when TRAIL-R1 but not TRAIL-R2 was blocked. Overexpression of TRAF2 or Bcl-xL strongly increased TRAIL-mediated upregulation of uPA and IL-8. CONCLUSIONS: In PDAC cells, TRAIL strongly induced uPA and IL-8 via TRAIL-R1. This response was further enhanced in cells overexpressing TRAF2 and Bcl-xL. Therefore, inhibition of the non-apoptotic "side-effects" of TRAIL treatments by inactivation of TRAF2 and Bcl-xL might represent additional relevant strategies for the treatment of pancreatic cancer.

24 Article Myofibroblast-induced tumorigenicity of pancreatic ductal epithelial cells is L1CAM dependent. 2012

Schäfer, Heiner / Geismann, Claudia / Heneweer, Carola / Egberts, Jan-Hendrik / Korniienko, Olena / Kiefel, Helena / Moldenhauer, Gerhard / Bachem, Max G / Kalthoff, Holger / Altevogt, Peter / Sebens, Susanne. ·Department of Internal Medicine I, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, 24105 Kiel, Germany. ·Carcinogenesis · Pubmed #22095073.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis, representing one risk factor for PDAC, are characterized by a marked desmoplasia enriched of pancreatic myofibroblasts (PMFs). Thus, PMFs are thought to essentially promote pancreatic tumorigenesis. We recently demonstrated that the adhesion molecule L1CAM is involved in epithelial-mesenchymal transition of PMF-cocultured H6c7 human ductal epithelial cells and that L1CAM is expressed already in ductal structures of chronic pancreatitis with even higher elevation in primary tumors and metastases of PDAC patients. This study aimed at investigating whether PMFs and L1CAM drive malignant transformation of pancreatic ductal epithelial cells by enhancing their tumorigenic potential. Cell culture experiments demonstrated that in the presence of PMFs, H6c7 cells exhibit a profound resistance against death ligand-induced apoptosis. This apoptosis protection was similarly observed in H6c7 cells stably overexpressing L1CAM. Intrapancreatic inoculation of H6c7 cells together with PMFs (H6c7co) resulted in tumor formation in 7/8 and liver metastases in 6/8 severe combined immunodeficiency (SCID) mice, whereas no tumors and metastases were detectable after inoculation of H6c7 cells alone. Likewise, tumor outgrowth and metastases resulted from inoculation of L1CAM-overexpressing H6c7 cells in 5/7 and 3/7 SCID mice, respectively, but not from inoculation of mock-transfected H6c7 cells. Treatment of H6c7co tumor-bearing mice with the L1CAM antibody L1-9.3/2a inhibited tumor formation and liver metastasis in 100 and 50%, respectively, of the treated animals. Overall, these data provide new insights into the mechanisms of how PMFs and L1CAM contribute to malignant transformation of pancreatic ductal epithelial cells in early stages of pancreatic tumorigenesis.

25 Article Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma. 2012

Sperveslage, Jan / Frank, Sunna / Heneweer, Carola / Egberts, Jan / Schniewind, Bodo / Buchholz, Malte / Bergmann, Frank / Giese, Nathalia / Munding, Johanna / Hahn, Stephan A / Kalthoff, Holger / Klöppel, Günter / Sipos, Bence. ·Institute of Pathology, University of Tübingen, Tübingen, Germany. ·Int J Cancer · Pubmed #22020953.

ABSTRACT: CCR7 expression on tumor cells promotes lymphatic spread in several malignant tumors. However, a comprehensive characterization of the CCL19/CCL21-CCR7 axis in pancreatic ductal adenocarcinoma (PDAC), which is known for its high rates of lymph-node metastases, is still lacking. CCR7 mRNA and CCR7 protein were found to be expressed in spheroid cultures of all six examined PDAC cell lines. In migration assays, CCR7 expressing PDAC cells showed enhanced migration toward CCL19 and CCL21, the two ligands of CCR7. In an orthotopic nude mouse model, CCR7-transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph vessel invasion and lymph-node metastases than mock-transfected cells. In an analysis using quantitative real-time PCR, CCR7 showed fourfold overexpression in microdissected PDAC cells compared to normal duct cells. Moderate-to-strong immunohistochemical CCR7 expression, found in 58 of 121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph-node metastases. The evaluation of CCL21 expression by immunofluorescence staining revealed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared to lymph vessels in disease-free pancreata. In conclusion, our study revealed strong evidence that lack of CCR7 impairs the metastatic potential of PDAC. Lymph vessel invasion by CCR7 expressing PDAC cells may be additionally enhanced by upregulation of CCL21 in tumor-associated lymph vessels, representing a previously unknown factor of lymphatic spread.

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