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

Sascha Rahn, Vivien Zimmermann, Fabrice Viol, Hendrike Knaack, Kerstin Stemmer, Lena Peters, Lennart Lenk, Hendrik Ungefroren, Dieter Saur, Heiner Schäfer, Ole Helm, Susanne Sebens

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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.

Original languageEnglish
Pages (from-to)129-150
Number of pages22
JournalCancer Letters
Volume415
DOIs
StatePublished - 28 Feb 2018
Externally publishedYes

Keywords

  • Cancer stemness
  • Diabetes
  • EMT
  • Glucose
  • Pancreatic cancer

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