RAGE Gene Deletion Inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Mouse Model of Pancreatic Cancer
Joseph Dinorcia*1, Minna K. Lee1, Dorota N. Moroziewicz1, Megan D. Winner1, Paritosh Suman1, Fei BAO3, Helen Remotti3, Yu Shan Zou2, Shi Fang Yan2, Wanglong Qiu1, Gloria H. Su1, Ann Marie Schmidt2, John D. Allendorf1
1Surgery, Columbia University College of Physicians and Surgeons, New York, NY; 2Medicine, New York University Langone Medical Center, New York, NY; 3Pathology, Columbia University Medical Center, New York, NY
Background: Activating Kras mutations and inactivation of the p16 tumor suppressor gene are commonly present in pancreatic ductal adenocarcinoma. The receptor for advanced glycation end-products (RAGE) is a cell surface receptor implicated in carcinogenesis. Objective: The aim of this study was to evaluate the effect of Rage gene deletion on the development and progression of pancreatic ductal neoplasia in a conditional KrasG12D, conventional p16 knockout mouse line. Materials and Methods: To evaluate the impact of Rage deletion on pancreatic intraepithelial neoplasia (PanIN), Pdx-1-Cre/KrasG12D mice were crossed with Rage-/- mice in the C57BL/6 background to generate Pdx-1-Cre/KrasG12D/Rage-/- mice. To evaluate the impact on pancreatic ductal adenocarcinoma (PDAC), Pdx-1-Cre/KrasG12D/p16-/- mice were crossed with Rage-/- mice to generate Pdx-1-Cre/KrasG12D/p16-/-/Rage-/- mice. Mice were sacrificed and pancreata were procured for scoring of ductal neoplasia compared to Pdx-1-Cre/KrasG12D or Pdx-1-Cre/KrasG12D/p16-/- controls. To evaluate the impact on survival, mice were aged to their natural death, and Kaplan-Meier analysis was performed. Categorical variables were compared using Fisher’s exact test, and median survivals were compared with the log-rank test.Results: At 16 weeks of age, Pdx-1-Cre/KrasG12D/Rage-/- mice had significantly fewer PanIN2 and PanIN3 lesions compared to controls (5.7% vs. 14.9%, p=0.0024). At 12 weeks of age, Pdx-1-Cre/KrasG12D/p16-/-/Rage-/- mice had significantly fewer PanIN2 and PanIN3 lesions compared to controls (10.6% vs. 18.9%, p=0.0033). Strikingly, none of the Pdx-1-Cre/KrasG12D/p16-/-/Rage-/- mice had invasive PDAC compared to a 45.5% incidence of invasive PDAC in controls (p=0.0411). Finally, Pdx-1-Cre/KrasG12D/p16-/-/Rage-/- mice had markedly longer median survival than controls (20.9 weeks vs. 16.0 weeks, p=0.0012). Conclusion: RAGE signaling inhibition significantly reduced the development of pancreatic neoplasms and significantly prolonged survival in this mouse model of pancreatic cancer. Further work is needed to target the ligand-RAGE axis for possible prophylaxis and treatment of pancreatic cancer.
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