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Rahn, S.* ; Zimmermann, V.* ; Viol, F.* ; Stemmer, K. ; Peters, L.* ; Lenk, L.* ; Ungefroren, H.* ; Saur, D.* ; Schäfer, H.* ; Helm, O.* ; Sebens, S.*

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

Cancer Lett. 415, 129-150 (2018)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 Pancl 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-betal (TGF-beta 1) as well as TGF-beta 1 signaling, and in a TGF-beta 1-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-beta signaling and might explain how T2DM facilitates pancreatic tumorigenesis. (C) 2017 Elsevier B.V. All rights reserved.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Pancreatic Cancer ; Diabetes ; Glucose ; Cancer Stemness ; Emt; High Glucose Promotes; Tgf-beta; Signaling Pathway; Up-regulation; Cardiac Fibroblasts; Calorie Restriction; Carcinoma-cells; Mouse Model; K-ras; Adenocarcinoma
Language english
Publication Year 2018
Prepublished in Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0304-3835
e-ISSN 0304-3835
Journal Cancer Letters
Quellenangaben Volume: 415, Issue: , Pages: 129-150 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Clare
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-501900-221
DOI 10.1016/j.canlet.2017.12.004
WOS ID WOS:000424725600012
Scopus ID 85037872017
PubMed ID 29222037
Erfassungsdatum 2018-01-24
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