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RAGE Gene Deletion Inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Murine Model of Pancreatic Cancer

  • 2011 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

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.

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Acknowledgments

This work was generously supported by the I.W. Foundation and an institutional Ruth L. Kirschstein National Research Service Award (T32 HL 007854–14).

Author information

Authors and Affiliations

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

    Joseph DiNorcia, Minna K. Lee, Dorota N. Moroziewicz, Megan Winner, Paritosh Suman, Gloria H. Su & John D. Allendorf

  2. College of Physicians and Surgeons, Department of Pathology, Columbia University, New York, NY, USA

    Fei Bao & Helen E. Remotti

  3. College of Physicians and Surgeons, Department of Otolaryngology and Head and Neck Surgery, Columbia University, New York, NY, USA

    Wanglong Qiu & Gloria H. Su

  4. Langone Medical Center, Department of Medicine, New York University, New York, NY, USA

    Yu Shan Zou, Shi Fang Yan & Ann Marie Schmidt

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  1. Joseph DiNorcia
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Correspondence to John D. Allendorf.

Additional information

Discussant

Dr. Emina H. Huang (Gainesville, FL): Congratulations, Dr. DiNorcia, for continued excellent work under the guidance of Drs. Ann Marie Schmidt and John Allendorf. Your presentation today is the culmination of a tremendous labor of breeding, genotyping, and pathologic dissection and you are commended for your efforts.

In your discussion, you refer to the issues that mechanism in your studies is only inferred. With the recent advances in combining molecular pathways and signatures from malignancies such as melanoma and non-small cell lung cancer in efforts to provide targeted treatment, I have three questions:

1. Are either soluble RAGE or a RAGE small molecule inhibitor, or cromolyn or other S100P antagonists potential treatments for pancreatic cancer?

2. Have you tried these interventions early on in the Tuveson mouse model?

3. Do you see a role for RAGE antagonism in those kindred with a familial pancreatic cancer or for those lacking metastatic disease, to prevent either metastases or recurrence?

Again, brilliant work and congratulations!

Closing Discussant

Dr. Joseph DiNorcia: Thank you, Dr. Huang, for your gracious comments and questions. RAGE inhibitors may be potential treatments for pancreatic cancer. It also is possible to envision inhibitors of downstream signaling as potential treatments once these post-receptor pathways are better defined. Given the complex role RAGE plays in differentially regulating cell survival and cell death, we have considerable more work to do prior to clinical application.

Targeting the ligand–RAGE axis also may be a strategy to improve the effectiveness of chemotherapy. For example, it has been shown that HMGB1 is released following tumor cell death and interacts with RAGE on neighboring tumor cells to promote survival. By inhibiting this ligand–RAGE interaction, we might be able to enhance a chemotherapeutic agent's ability to kill tumor cells.

We have treated a very small number of Pdx1-Cre; Kras G12D/+; p16 Ink4a−/− mice with sRAGE. Although we noted no differences in the incidence of carcinoma, there was a significantly decreased stromal reaction in sRAGE-treated mice compared to controls, suggesting that stromal cells play roles in tumorigenesis via RAGE-dependent pathways.

Finally, perhaps the most practical clinical application of RAGE antagonism is in pancreatic cancer prevention. For example, RAGE inhibition in patients with IPMN may delay or arrest tumor progression to carcinoma. Or, in patients with localized pancreatic cancer, RAGE antagonism may prevent invasion and metastases by inhibiting tumor cell adhesion and motility. The ligand–RAGE axis is an attractive target for potential prophylaxis and treatment of pancreatic cancer and thus remains an exciting area for further study.

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DiNorcia, J., Lee, M.K., Moroziewicz, D.N. et al. RAGE Gene Deletion Inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Murine Model of Pancreatic Cancer. J Gastrointest Surg 16, 104–112 (2012). https://doi.org/10.1007/s11605-011-1754-9

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  • DOI: https://doi.org/10.1007/s11605-011-1754-9

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