TY - JOUR
T1 - Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression
AU - Mohammed, Altaf
AU - Janakiram, Naveena B.
AU - Madka, Venkateshwar
AU - Brewer, Misty
AU - Ritchie, Rebekah L.
AU - Lightfoot, Stan
AU - Kumar, Gaurav
AU - Sadeghi, Michael
AU - Patlolla, Jagan Mohan R.
AU - Yamada, Hiroshi Y.
AU - Cruz-Monserrate, Zobeida
AU - May, Randal
AU - Houchen, Courtney W.
AU - Steele, Vernon E.
AU - Rao, Chinthalapally V.
PY - 2015
Y1 - 2015
N2 - 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. Genomewide 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.
AB - 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. Genomewide 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.
KW - Cancer stem cells
KW - Dual COX-5-LOX inhibition
KW - Inflammation
KW - P48-LSL-Kras mice
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=84934343399&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3499
DO - 10.18632/oncotarget.3499
M3 - Article
C2 - 25906749
AN - SCOPUS:84934343399
SN - 1949-2553
VL - 6
SP - 15524
EP - 15539
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -