Research Papers:
Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 3064 views | HTML 2707 views | ?
Abstract
Altaf Mohammed1,*, Naveena B. Janakiram1,*, Venkateshwar Madka1, Misty Brewer1, Rebekah L. Ritchie1, Stan Lightfoot1, Gaurav Kumar1, Michael Sadeghi1, Jagan Mohan R. Patlolla1, Hiroshi Y. Yamada1, Zobeida Cruz-Monserrate2, Randal May3, Courtney W. Houchen3, Vernon E. Steele4, Chinthalapally V. Rao1
1Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
2Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
3Digestive Diseases Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
4Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, MD, USA
*These authors have contributed equally to this work
Correspondence to:
Chinthalapally V. Rao, e-mail: [email protected]
Altaf Mohammed, e-mail: [email protected]
Keywords: pancreatic cancer, inflammation, dual COX-5-LOX inhibition, cancer stem cells, p48Cre/+-LSL-KrasG12D/+ mice
Received: March 03, 2015 Accepted: March 07, 2015 Published: March 26, 2015
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.
![Creative Commons License](/images/80x15.png)
PII: 3499