Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression

Oncotarget. 2015 Jun 20;6(17):15524-39. doi: 10.18632/oncotarget.3499.

Abstract

Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients.

Keywords: cancer stem cells; dual COX-5-LOX inhibition; inflammation; p48Cre/+-LSL-KrasG12D/+ mice; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Apoptosis / drug effects
  • Arachidonic Acid / metabolism
  • Carcinoma in Situ / pathology
  • Carcinoma in Situ / prevention & control
  • Carcinoma, Pancreatic Ductal / pathology*
  • Carcinoma, Pancreatic Ductal / prevention & control
  • Cell Proliferation / drug effects
  • Ceruletide
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Lipoxygenase Inhibitors / pharmacology
  • Mice
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors
  • Neoplastic Stem Cells / pathology*
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / prevention & control
  • Pancreatitis / chemically induced
  • Pancreatitis / pathology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrroles / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Lipoxygenase Inhibitors
  • MicroRNAs
  • Pyrroles
  • Arachidonic Acid
  • Ceruletide
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dcamkl1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • licofelone