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01-01-2012 | 2011 SSAT Plenary Presentation

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

Authors: Joseph DiNorcia, Minna K. Lee, Dorota N. Moroziewicz, Megan Winner, Paritosh Suman, Fei Bao, Helen E. Remotti, Yu Shan Zou, Shi Fang Yan, Wanglong Qiu, Gloria H. Su, Ann Marie Schmidt, John D. Allendorf

Published in: Journal of Gastrointestinal Surgery | Issue 1/2012

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.

Jemal A, Siegel R., Xu J, Ward E. Cancer statistics, 2010. CA cancer J Clin 2010;60:277–300.PubMedCrossRef

Maitra A, Fukushima N, Takaori K, Hruban RH. Precurors to invasive pancreatic cancer. Adv Anat Pathol 2005;12:81–91.PubMedCrossRef

Hruban RH, Goggins M, Parsons J, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol 2000;156:1821–1825.PubMedCrossRef

Hingorani SR, Petrcoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Wright CVE, Hruban RH, Lowy AM, Tuveson DA. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer cell 2003;4:437–450.PubMedCrossRef

Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, Feng B, Brennan C, Weissleder R, Mahmood U, Hanahan D, Redston MS, Chin L, DePinho RA. Both p16^Ink4a and the p19^Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. PNAS 2006;103:5947–5952.PubMedCrossRef

Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes & Dev 2003;17:3112–3126.CrossRef

Bardessy N, Morgan J, Sinha M, Signoretti S, Srivastava S, Loda M, Merlino G, DePinho RA. Obligate roles for p16Ink4a and p19Arf-p53 in the suppression of murine pancreatic neoplasia. Mol Cell Biol 2002;22:635–643.CrossRef

Han SH, Kim YH, Mook-Jung I. RAGE: The beneficial and deleterious effects by diverse mechanisms of actions. Mol Cells 2011;31:91–97.PubMedCrossRef

Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P, Bierhaus A, Lotze MT, Zeh HJ. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis promoting pancreatic tumor cell survival. Cell Death Differ 2010;17:666–676.PubMedCrossRef

10.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436–444.PubMedCrossRef

11.

Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009;457:102–107.PubMedCrossRef

12.

Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001;108:949–955.PubMed

13.

Logsdon CD, Fuentes MK, Huang EH, Arumugam T. RAGE and RAGE ligands in cancer. Curr Mol Med 2007;7:777–789.PubMedCrossRef

14.

Riehl A, Németh J, Angel P, Hess J. The receptor RAGE: bridging inflammation and cancer. Cell Comm Sig 2007;7:12.CrossRef

15.

Rojas A, Figueroa H, Morales E. Fueling inflammation at tumor microenvironment: the role of multiligand/RAGE axis. Carcinogenesis 2010;31:334–341.PubMedCrossRef

16.

Ramasamy R, Yan SF, Schmidt AM. RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J Leukoc Biol 2009;86:505–512.PubMedCrossRef

17.

Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010;28:367–388.PubMedCrossRef

18.

Takada M, Koizumi T, Toyama H, Suzuki Y, Kuroda Y. Differential expression of RAGE in human pancreatic carcinoma cells. Hepatogastroenterology 2001;48:1577–1578.PubMed

19.

Takada M, Hirata K, Ajiki T, Suzuki Y, Kuroda Y. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells. Hepatogastroenterology 2004;51:928–930.PubMed

20.

Krechler T, Jachymova M, Mestek O, Zak A, Zima T, Kalousova M. Soluble receptor for advanced glycation end-products (sRAGE) and polymorphisms or RAGE and glyoxalase I genes in patients with pancreas cancer. Clin Biochem 2010;43:882–886.PubMedCrossRef

21.

Whiteman HJ, Weeks ME, Dowen SE, Barry S, Timms JF, Lemoine NR, Crnogorac-Jurcevic T. The role of S100P in the invasion of pancreatic cancer cells is mediated through cytoskeletal changes and regulation of cathepsin D. Cancer Res 2007;67:8633–8642.PubMedCrossRef

22.

DiNorcia J, Moroziewicz DN, Ippagunta N, Lee MK, Foster M, Rotterdam HZ, Bao F, Zou YS, Yan SF, Emond J, Schmidt AM, Allendorf JD. RAGE signaling significantly impacts tumorigenesis and hepatic tumor growth in murine models of colorectal carcinoma. J Gastrointest Surg 2010;14:1680–90.PubMedCrossRef

23.

Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes & Dev 2001;15:3243–3248.CrossRef

24.

Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA. Loss of p16^Ink4a with retention of p19^Arf predisposes mice to tumorigenesis. Nature 2001;413:86–91.PubMedCrossRef

25.

Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus. A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D'Agati VD, Schmidt AM. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003;162:1123–1137.PubMedCrossRef

26.

Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 2003;111:959–972.PubMed

27.

Funahashi H, Satake M, Dawson D, Huynh NA, Reber HA, Hines OJ, Eibl G. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras^G12D mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res 2007;67:7068–7071.PubMedCrossRef

28.

Hruban RH, Rustgi AK, Brentnall TA, Tempero MA, Wright CV, Tuveson DA. Pancreatic cancer in mice and man: the Penn Workshop 2004. Cancer Res 2006;66:14–7.PubMedCrossRef

29.

Hruban RH, Adsay NV, Albores-Saavedra J, Anver MR, Biankin AV, Boivin GP, Furth EE, Furukawa T, Klein A, Klimstra DS, Kloppel G, Lauwers GY, Longnecker DS, Luttges J, Maitra A, Offerhaus GJ, Perez-Gallego L, Redston M, Tuveson DA. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 2006;66:95–106.PubMedCrossRef

30.

Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hor O, Ogawa S, Stern DM, Schmidt AM. Blockade of amphoterin/RAGE signaling suppresses tumor growth and metastases. Nature 2001;405:354–360.

31.

Shi G, Shu L, Sun Y, Bettencourt R, Damsz B, Hruban RH, Konieczny SF. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 2009;136:1328–1378.CrossRef

32.

Lee KE, Bar-Sagi D. Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 2010;18:448–458.PubMedCrossRef

33.

Fendrich V, Schneider R, Maitra A, Jacobsen ID, Opfermann T, Bartsch DK. Detection of precursor lesions of pancreatic adenocarcinoma in PET-CT in a genetically engineered mouse model of pancreatic cancer. Neoplasia 2011;13:180–186.PubMed

34.

Rowley M, Ohashi A, Mondal G, Mills L, Yang L, Zhang L, Sundsbak R, Shapiro V, Muders MH, Smyrk T, Couch FJ. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology 2011;140:1303–1313.PubMedCrossRef

35.

Hill R, Calvopina JH, Kim C, Wang Y, Dawson DW, Donahue TR, Dry S, Wu H. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res 2010;70:2114–7124.CrossRef

36.

Mohammed A, Janakiram NB, Li Q, Madka V, Ely M, Lightfoot S, Crawford H, Steele VE, Rao CV. The epidermal growth factor receptor inhibitor Gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-Kras^G12D/+ transgenic mouse model. Cancer Prev Res 2010;3:1417–1426.CrossRef

37.

Arumugam T, Simeone DM, Van Golen K, Logsdon CD. S100P promotes pancreatic cancer growth, survival, and invasion. Clin Cancer Res 2005;11:5356–5364.PubMedCrossRef

38.

Arumugam T, Ramachandran V, Logsdon CD. Effect of cromolyn on S100P interactions with RAGE and pancreatic cancer growth and invasion in mouse models. J National Cancer Inst 2006;98:1806–1818.CrossRef

39.

Kostova N, Zlateva S, Ugrinova I, Pasheva E. The expression of HMGB1 protein and its receptor RAGE in human malignant tumors. Mol Cell Biochem 2010;337:251–258.PubMedCrossRef

40.

Tang D, Lotze MT, Zeh HJ, Kang R. The redox protein HMGB1 regulates cell death and survival in cancer treatment. Autophagy 2010;16:1181–1183.CrossRef

Title: RAGE Gene Deletion Inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Murine Model of Pancreatic Cancer
Authors: Joseph DiNorcia
Minna K. Lee
Dorota N. Moroziewicz
Megan Winner
Paritosh Suman
Fei Bao
Helen E. Remotti
Yu Shan Zou
Shi Fang Yan
Wanglong Qiu
Gloria H. Su
Ann Marie Schmidt
John D. Allendorf
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 1/2012
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-011-1754-9

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Objective

Materials and Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Objective

Materials and Methods

Results

Conclusion

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