title: Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer.
abstract: Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy.
authors.affiliation: Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA.
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaida
authors.affiliation: Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA.
authors.forename: Shouhui
authors.initials: S
authors.lastname: Yang
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany.
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.affiliation: Genetics Branch, CCR, NCI, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Harris
authors.initials: H
authors.lastname: Yfantis
authors.affiliation: Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Lee
authors.affiliation: Cancer and Inflammation Program, CCR, NCI Frederick, MD, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Laboratory of Cell and Developmental Signaling, NCI Frederick, MD, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Stauffer
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.affiliation: Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA.
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: KPC mouse model; NO; NOS2; PDAC