title: RAGE gene deletion inhibits the development and progression of ductal neoplasia and prolongs survival in a murine model of pancreatic cancer.
abstract: BACKGROUND
  The receptor for advanced glycation end-products (RAGE) is implicated in pancreatic tumorigenesis. Activating Kras mutations and p16 inactivation are genetic abnormalities most commonly detected as pancreatic ductal epithelium progresses from intraepithelial neoplasia (PanIN) to adenocarcinoma (PDAC).
  
  
  OBJECTIVE
  The aim of this study was to evaluate the effect of RAGE (or AGER) deletion on the development of PanIN and PDAC in conditional Kras                            (                               G12D                            ) mice.
  
  
  METHODS
  Pdx1-Cre; LSL-Kras                            (                               G12D/+) mice were crossed with RAGE                            (-/-) mice to generate Pdx1-Cre; LSL-Kras                            (                               G12D/+)                            ; RAGE                            (-/-) mice. Pdx1-Cre; LSL-Kras                            (                               G12D/+); p16                            (                               Ink4a-/-) mice were crossed with RAGE                            (-/-) mice to generate Pdx1-Cre; LSL-Kras                            (                               G12D/+); p16                            (                               Ink4a-/-); RAGE                            (-/-) mice. Pancreatic ducts were scored and compared to the relevant RAGE                            (+/+) controls.
  
  
  RESULTS
  At 16 weeks of age, Pdx1-Cre; LSL-Kras                            (                               G12D/+); RAGE                            (-/-) mice had significantly fewer high-grade PanIN lesions than Pdx1-Cre; LSL-Kras                            (                               G12D/+); RAGE                            (+/+) controls. At 12 weeks of age, none of the Pdx1-Cre; LSL-Kras                            (                               G12D/+); p16                            (                               Ink4a-/-); RAGE                            (-/-) mice had PDAC compared to a 45.5% incidence of PDAC in Pdx1-Cre; LSL-Kras                            (                               G12D/+); p16                            (                               Ink4a-/-); RAGE                            (+/+) controls. Finally, Pdx1-Cre; LSL-Kras                            (                               G12D/+); p16                            (                               Ink4a-/-); RAGE                            (-/-) mice also displayed markedly longer median survival.
  
  
  CONCLUSIONS
  Loss of RAGE function inhibited the development of PanIN and progression to PDAC and significantly prolonged survival in these mouse models. Further work is needed to target the ligand-RAGE axis for possible early intervention and prophylaxis in patients at risk for developing pancreatic cancer.
authors: College of Physicians and Surgeons, Department of Surgery, Columbia University, 161 Fort Washington Avenue, Suite 820, New York, NY 10032-3784, USA.
authors: Joseph
authors: J
authors: DiNorcia
authors: Minna K
authors: MK
authors: Lee
authors: Dorota N
authors: DN
authors: Moroziewicz
authors: Megan
authors: M
authors: Winner
authors: Paritosh
authors: P
authors: Suman
authors: Fei
authors: F
authors: Bao
authors: Helen E
authors: HE
authors: Remotti
authors: Yu Shan
authors: YS
authors: Zou
authors: Shi Fang
authors: SF
authors: Yan
authors: Wanglong
authors: W
authors: Qiu
authors: Gloria H
authors: GH
authors: Su
authors: Ann Marie
authors: AM
authors: Schmidt
authors: John D
authors: JD
authors: Allendorf
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D017353:Gene Deletion; D053208:Kaplan-Meier Estimate; D051379:Mice; D023421:Models, Animal; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016012:Poisson Distribution; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic