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.
Highlights
Despite tremendous scientific effort for over three decades, pancreatic cancer (PC) remains a devastating, almost uniformly lethal disease with < 5% five-year survival
Activation of inflammation and cancer stem cells (CSC) during progression of pancreatic cancer p48Cre/+-LSL-KrasG12D/+ mice were analyzed for the expression of COX-2, 5-LOX and DclK1 (Fig. 1, Supplementary Fig. 1)
As the mice aged from 2 to 6 to 10 months, along with progression of pancreatic www.impactjournals.com/oncotarget intra-epithelial neoplasia (PanIN) lesions and carcinoma, we observed a significant increase in the inflammatory COX-2 along with proliferating cells (Fig. 1A-1C, Supplementary Fig. 1)
Summary
Despite tremendous scientific effort for over three decades, pancreatic cancer (PC) remains a devastating, almost uniformly lethal disease with < 5% five-year survival. Recent studies demonstrate that pre-invasive precursors progress slowly over many years to decades to development of invasive PCs [1,2,3]. Premalignant pancreatic www.impactjournals.com/oncotarget intra-epithelial neoplasia (PanIN) lesions are the most common precursors to invasive PDAC, rendering them promising targets for intervention, especially in the high-risk population [4]. Several genetically engineered mouse models (GEMs) of PC have been developed that recapitulate human disease progression. It was demonstrated recently that the KrasG12Ddependent mouse model of PDAC that accurately mimics the therapeutic response of human PDAC offers the opportunity to develop novel treatments [3, 9,10,11]. We have shown that these GEM are excellent models for understanding PanIN progression and are useful for drug and other intervention studies [3, 12,13,14,15,16,17,18]
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