Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. (28th February 2018)

• Record Type: Journal Article
• Authors: Rahn, Sascha; Zimmermann, Vivien; Viol, Fabrice; Knaack, Hendrike; Stemmer, Kerstin; Peters, Lena; Lenk, Lennart; Ungefroren, Hendrik; Saur, Dieter; Schäfer, Heiner; Helm, Ole; Sebens, Susanne
• Is Part Of: Cancer letters. Volume 415(2018)
• Page Start: 129
• Page End: 150
• Publication Date: 2018-02-28
• Subjects: Pancreatic cancer -- Diabetes -- Glucose -- Cancer stemness -- EMT; CFA Colony formation assay -- CSC Cancer stem cells -- EMT Epithelial-Mesenchymal-Transition -- GAPDH Glycerol-3-phosphate dehydrogenase -- Hsp90 Heat shock protein 90 -- PanIN Pancreatic Intraepithelial Neoplasia -- PDAC Pancreatic ductal adenocarcinoma -- PDEC pancreatic ductal epithelial cells -- TBP TATA box-binding protein -- TGF-β1 Transforming Growth Factor-beta 1 -- T2DM Type 2 diabetes mellitus; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.12.004
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Elevated glucose levels aggravate cancer stemness in pancreatic cancer cells. Hyperglycemia essentially impacts already on pancreatic ductal epithelial cells. Hyperglycemia-induced mesenchymal and CSC-properties are TGF-β1 dependent. This study gives insight how hyperglycemia contributes to pancreatic tumorigenesis.