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

被引：35

作者：

Mohammed, Altaf ^{[1
]}

Janakiram, Naveena B. ^{[1
]}

Madka, Venkateshwar ^{[1
]}

Brewer, Misty ^{[1
]}

Ritchie, Rebekah L. ^{[1
]}

Lightfoot, Stan ^{[1
]}

Kumar, Gaurav ^{[1
]}

Sadeghi, Michael ^{[1
]}

Patlolla, Jagan Mohan R. ^{[1
]}

Yamada, Hiroshi Y. ^{[1
]}

Cruz-Monserrate, Zobeida ^{[2
]}

May, Randal ^{[3
]}

Houchen, Courtney W. ^{[3
]}

Steele, Vernon E. ^{[4
]}

Rao, Chinthalapally V. ^{[1
]}

机构：

[1] Univ Oklahoma, Hlth Sci Ctr, PC Stephenson Canc Ctr, Ctr Canc Prevent & Drug Dev,Dept Med,Hemonc Sect, Oklahoma City, OK 73106 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[3] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Digest Dis Sect, Oklahoma City, OK USA

[4] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA

来源：

ONCOTARGET | 2015年 / 6卷 / 17期

关键词：

pancreatic cancer; inflammation; dual COX-5-LOX inhibition; cancer stem cells; p48(Cre/+)-LSL-Kras(G12D/+) mice; ENGINEERED MOUSE MODELS; INTRAEPITHELIAL NEOPLASIA; PREVENTS PROGRESSION; ARACHIDONIC-ACID; INHIBITOR; LICOFELONE; CARCINOMA; CELECOXIB; MICRORNA; CYCLOOXYGENASE-2;

D O I：

10.18632/oncotarget.3499

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：15524 / 15539

页数：16

共 50 条

[1] MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES [J].