Oncotarget

Research Papers:

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

Altaf Mohammed _, Naveena B. Janakiram, Venkateshwar Madka, Misty Brewer, Rebekah L. Ritchie, Stan Lightfoot, Gaurav Kumar, Michael Sadeghi, Jagan Mohan R. Patlolla, Hiroshi Y. Yamada, Zobeida Cruz-Monserrate, Randal May, Courtney W. Houchen, Vernon E. Steele and Chinthalapally V. Rao

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Oncotarget. 2015; 6:15524-15539. https://doi.org/10.18632/oncotarget.3499

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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.


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