Reference SummaryVernon PJ, J Immunol 2013 Feb 1;190(3):1372-9

Title

The receptor for advanced glycation end products promotes pancreatic carcinogenesis and accumulation of myeloid-derived suppressor cells.

Authors

Vernon PJ; Loux TJ; Schapiro NE; Kang R; Muthuswamy R; Kalinski P; Tang D; Lotze MT; Zeh HJ 3rd

Journal

J Immunol

Volume

190

Issue

3

Year

2013

Pages

1372-9

Abstract

Pancreatic ductal adenocarcinoma (PDA) has an aggressive natural history and is resistant to therapy. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor for many damage-associated molecular pattern molecules. RAGE is overexpressed in both human and murine models of PDA as well as most advanced epithelial neoplasms. The immunosuppressive nature of the PDA microenvironment is facilitated, in part, by the accumulation of regulatory immune cell infiltrates such as myeloid-derived suppressor cells (MDSCs). To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple-transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice had markedly delayed pancreatic carcinogenesis and a significant diminution of MDSCs compared with KC mice at comparable time points postweaning. Although RAGE was not required for the development or suppressor activity of MDSCs, its absence was associated with temporally limited pancreatic neoplasia and altered phenotype and function of the myeloid cells. In lieu of MDSCs, KCR animals at comparable time points exhibited mature CD11b(+)Gr1(-)F4/80(+) cells that were not immunosuppressive in vitro. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.

Links

23269246 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129S-Agertm1.1Arnd Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct atypia Pancreas - Duct

observed

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct atypia Pancreas - Duct

observed

B6;129S-Agertm1.1Arnd Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct dysplasia Pancreas - Duct

observed

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct dysplasia Pancreas - Duct

observed

B6;129S-Agertm1.1Arnd Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct hyperplasia - epithelial Pancreas - Duct

observed

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas - Duct hyperplasia - epithelial Pancreas - Duct

observed

C57BL/6NTac Pancreas pancreatic intraepithelial neoplasia (PanIN) Pancreas

0

B6;129S-Agertm1.1Arnd Pancreas pancreatic intraepithelial neoplasia (PanIN) Pancreas

0

B6;129S-Agertm1.1Arnd Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas pancreatic intraepithelial neoplasia (PanIN) Pancreas

0

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas pancreatic intraepithelial neoplasia (PanIN) - high grade Pancreas

observed

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas pancreatic intraepithelial neoplasia (PanIN) - low grade Pancreas

observed

C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Pancreas preneoplastic lesion Pancreas

observed