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J Gastrointest Surg. 2012 Jan;16(1):104-12; discussion 112. doi: 10.1007/s11605-011-1754-9. Epub 2011 Nov 4.

RAGE gene deletion inhibits the development and progression of ductal neoplasia and prolongs survival in a murine model of pancreatic cancer.

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1
College of Physicians and Surgeons, Department of Surgery, Columbia University, 161 Fort Washington Avenue, Suite 820, New York, NY 10032-3784, USA.

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.

MATERIALS AND 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.

CONCLUSION:

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.

PMID:
22052106
PMCID:
PMC4049447
DOI:
10.1007/s11605-011-1754-9
[Indexed for MEDLINE]
Free PMC Article

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