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  • 1
    Abstract: OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated KrasG12D-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico. RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 27646934
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  • 2
    Abstract: Hypoxia-inducible factor 1alpha (Hif1alpha) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1alpha accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1alpha has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1alpha expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1alpha in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1alpha protects PDAC cells from stress-induced cell deaths in both scenarios-in line with the general function Hif1alpha-its depletion leads to different oncogenic consequences. Hif1alpha depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1alpha in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1alpha inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy.
    Type of Publication: Journal article published
    PubMed ID: 27941931
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; CELL ; Germany ; PATHWAY ; TYROSINE KINASE ; TISSUES ; MICROARRAY DATA ; METASTASIS ; PATHOGENESIS ; RESECTION ; CANCER-CELLS ; MIGRATION ; adenocarcinoma ; CENTRAL-NERVOUS-SYSTEM ; pancreatic cancer ; SMOOTH-MUSCLE ; SERUM ; PANCREATIC-CANCER ; cell proliferation ; cell migration ; pancreatic ductal adenocarcinoma ; C-MET ; WELL ; EXPERIMENT ANNOTATIONS ; CONSCIOUS RATS ; DEVELOPMENTAL PATTERN ; HUMAN GASTROINTESTINAL-TRACT ; Neuromedin U ; Neuromedin U receptor ; PORCINE SPINAL-CORD ; SCATTER FACTOR
    Abstract: Neuromedin U (NmU) is a bioactive peptide, ubiquitously expressed in the gastrointestinal tract. Here, we analyzed the role of NmU in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. NmU and NmU receptor-2 mRNA were significantly overexpressed in PDAC and in metastatic tissues. NmU and NmU receptor-2 were localized predominantly in cancer cells. NmU serum levels decreased after tumor resection. Although NmU exerted no effects on cancer cell proliferation, it induced c-Met and a trend towards increased invasiveness as well as an increased hepatocyte growth factor (HGF)-mediated scattering. Thus, NmU may be involved in the HGF-c-Met paracrine loop regulating cell migration, invasiveness and dissemination of PDAC. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19118941
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  • 4
    Keywords: IN-VIVO ; MICE ; RAS ONCOGENE ; EGF RECEPTOR ; MOUSE MODEL ; TUMOR-SUPPRESSOR ; DUCTAL ADENOCARCINOMA ; TUMORIGENESIS ; PI3K ; C-RAF
    Abstract: Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
    Type of Publication: Journal article published
    PubMed ID: 23453624
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  • 5
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  129. Kongress der Deutschen Gesellschaft für Chirurgie; 20120424-20120427; Berlin; DOC12dgch355 /20120423/
    Publication Date: 2012-04-24
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-4632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-12-04
    Description: Endometrial cancer is the most common gynecologic malignancy, whose incidence rate is on the rise. However, the underlying mechanisms of endometrial cancer are not very clear yet. miRNAs have been considered to be playing important roles in malignant behavior. Here, miR-652 was significantly upregulated in endometrial cancer, which correlated with shorter overall survival and earlier recurrence. Moreover, overexpression of miR-652 in endometrial cancer cells promoted proliferation, migration, and invasion in vitro and facilitated tumor growth and metastasis in vivo . In contrast, downregulation of miR-652 in endometrial cancer cells inhibited these processes both in vitro and in vivo . Mechanistically, miR-652 promotes proliferation and metastasis through directly targeting RORA . Both mRNA and protein level of RORA were negatively related with miR-652 and overexpression of RORA can rescue the promotion effect of miR-652. Further experiments indicated miR-652 overexpression can activate the Wnt/β-catenin pathway and RORA can downregulate β-catenin and function as a tumor suppressor in endometrial cancer. Collectively, these findings demonstrate that miR-652 functions as an oncomir in endometrial cancer. Implications: This study suggests that the miR-652 is a critical regulator of proliferation and metastasis in endometrial cancer and may serve as a therapeutic target.
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 8
    Publication Date: 2018-02-22
    Description: Background ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non–small cell lung cancer (NSCLC) slated for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescent in situ hybridization (FISH). The present study investigated the driver mutation and clinicopathologic characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1 -rearranged cases. Patients and Methods Tumors from 26 discordant cases were analyzed for clinicopathologic characteristics, mutations in EGFR , KRAS , ERBB2 , BRAF , and PIK3CA ; fusions in ALK and RET ; and amplifications in MET , ERBB2 , and ROS1 . Results ROS1-rearranged NSCLCs were significantly more likely to be found in younger patients and at an advanced stage; they showed cribriform features, extracellular mucus, and psammoma bodies, whereas ROS1-discordant cases were found in older patients at a relatively early TNM stage and showed a lepidic growth pattern (all P 〈.001). Most of ROS1-rearranged NSCLCs were no concurrent mutation, whereas 73% of discordant cases harbored genetic aberrations, including EGFR and ERBB2 . Compared with general lung adenocarcinomas, ERBB-2 abnormality was disproportionately high in ROS1-discordant cases. Moreover, we optimized the scoring criteria for ROS1 IHC as “H score 〉150 and no concurrent mutations”; then the specificity was increased to 81.6%. Conclusions Compared with ROS1-rearranged cases, ROS1-discordant patients showed distinct clinical and morphologic features and often harbored another oncogenic driver alteration. The use of optimized screening criteria will increase the specificity of ROS1 antibody. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
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