Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells
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Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. / Rahn, Sascha; Zimmermann, Vivien; Viol, Fabrice; Knaack, Hendrike; Stemmer, Kerstin; Peters, Lena; Lenk, Lennart; Ungefroren, Hendrik; Saur, Dieter; Schäfer, Heiner; Helm, Ole; Sebens, Susanne.
in: CANCER LETT, Jahrgang 415, 28.02.2018, S. 129-150.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells
AU - Rahn, Sascha
AU - Zimmermann, Vivien
AU - Viol, Fabrice
AU - Knaack, Hendrike
AU - Stemmer, Kerstin
AU - Peters, Lena
AU - Lenk, Lennart
AU - Ungefroren, Hendrik
AU - Saur, Dieter
AU - Schäfer, Heiner
AU - Helm, Ole
AU - Sebens, Susanne
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2018/2/28
Y1 - 2018/2/28
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Line
KW - Cell Line, Tumor
KW - Diabetes Mellitus, Type 2
KW - Epithelial Cells
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Glucose
KW - Humans
KW - Hyperglycemia
KW - Male
KW - Mice, Inbred C57BL
KW - Neoplastic Stem Cells
KW - Pancreatic Ducts
KW - Pancreatic Neoplasms
KW - Risk Factors
KW - Transforming Growth Factor beta1
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.canlet.2017.12.004
DO - 10.1016/j.canlet.2017.12.004
M3 - SCORING: Journal article
C2 - 29222037
VL - 415
SP - 129
EP - 150
JO - CANCER LETT
JF - CANCER LETT
SN - 0304-3835
ER -