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Rage signalling promotes intestinal tumourigenesis

Oncogene volume 32, pages 1202–1206 (2013)Cite this article

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Abstract

Development of colon cancer is a multistep process that is regulated by intrinsic and extrinsic cellular signals. Extrinsic factors include molecular patterns that are derived from either pathogens (PAMPs) or cellular damage (DAMPs). These molecules can promote tumourigenesis by activation of the innate immune system, but the individual contribution of ligands and their receptors remains elusive. The receptor for advanced glycation end products (Rage) is a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment such as Hmgb1 and S100 protein. Here we show that Rage signalling has a critical role in sporadic development of intestinal adenomas, as ApcMin/+ Rage−/− mice are protected against tumourigenesis.

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References

  1. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285–296.

    Article  CAS  Google Scholar 

  2. Rakoff-Nahoum S, Medzhitov R . Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 2007; 317: 124–127.

    Article  CAS  Google Scholar 

  3. Ekbom A, Helmick C, Zack M, Adami HO . Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990; 323: 1228–1233.

    Article  CAS  Google Scholar 

  4. Ekbom A, Helmick C, Zack M, Adami HO . Increased risk of large-bowel cancer in Crohn′s disease with colonic involvement. Lancet 1990; 336: 357–359.

    Article  CAS  Google Scholar 

  5. Neufert C, Becker C, Neurath MF . An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc 2007; 2: 1998–2004.

    Article  CAS  Google Scholar 

  6. Fukata M, Shang L, Santaolalla R, Sotolongo J, Pastorini C, Espana C et al. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm Bowel Dis 2011; 17: 1464–1473.

    Article  Google Scholar 

  7. Turovskaya O, Foell D, Sinha P, Vogl T, Newlin R, Nayak J et al. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 2008; 29: 2035–2043.

    Article  CAS  Google Scholar 

  8. Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol 2001; 1: 135–145.

    Article  CAS  Google Scholar 

  9. van Zoelen MA, Achouiti A, van der Poll T . The role of receptor for advanced glycation endproducts (RAGE) in infection. Crit Care 2011; 15: 208.

    Article  Google Scholar 

  10. Lotze MT, Tracey KJ . High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5: 331–342.

    Article  CAS  Google Scholar 

  11. He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep 2011; 12: 358–364.

    Article  CAS  Google Scholar 

  12. Du YS, Zhu H, Fu J, Yan SF, Roher A, Tourtellotte WW et al. Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci USA 1997; 94: 5296–5301.

    Article  Google Scholar 

  13. Karin M, Greten FR . NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749–759.

    Article  CAS  Google Scholar 

  14. Moser AR, Pitot HC, Dove WF . A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990; 247: 322–324.

    Article  CAS  Google Scholar 

  15. Lee SH, Hu LL, Gonzalez-Navajas J, Seo GS, Shen C, Brick J et al. ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nat Med 2010; 16: 665–670.

    Article  CAS  Google Scholar 

  16. Volp K, Brezniceanu ML, Bosser S, Brabletz T, Kirchner T, Gottel D et al. Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas. Gut 2006; 55: 234–242.

    Article  CAS  Google Scholar 

  17. Kang HJ, Lee H, Choi HJ, Youn JH, Shin JS, Ahn YH et al. Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers. Lab Invest 2009; 89: 948–959.

    Article  CAS  Google Scholar 

  18. Salama I, Malone PS, Mihaimeed F, Jones JL . A review of the S100 proteins in cancer. Eur J Surg Oncol 2008; 34: 357–364.

    Article  CAS  Google Scholar 

  19. Heijmans J, Muncan V, Jacobs RJ, de Jonge-Muller ES, Graven L, Biemond I et al. Intestinal tumorigenesis is not affected by progesterone signaling in rodent models. PLoS ONE 2011; 6: e22620.

    Article  CAS  Google Scholar 

  20. Constien R, Forde A, Liliensiek B, Grone HJ, Nawroth P, Hammerling G et al. Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis 2001; 30: 36–44.

    Article  CAS  Google Scholar 

  21. Barker N, van Es JH, Kuipers J, Kujala P, van den BM, Cozijnsen M et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003–1007.

    Article  CAS  Google Scholar 

  22. Cole AM, Myant K, Reed KR, Ridgway RA, Athineos D, van den Brink GR et al. Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss. Cancer Res 2010; 70: 8149–8158.

    Article  CAS  Google Scholar 

  23. Sakaguchi M, Murata H, Yamamoto K, Ono T, Sakaguchi Y, Motoyama A et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS ONE 2011; 6: e23132.

    Article  CAS  Google Scholar 

  24. Gebhardt C, Riehl A, Durchdewald M, Nemeth J, Furstenberger G, Muller-Decker K et al. RAGE signaling sustains inflammation and promotes tumor development. J Exp Med 2008; 205: 275–285.

    Article  CAS  Google Scholar 

  25. Heijmans J, Buller NV, Muncan V, van den Brink GR . Role of mast cells in colorectal cancer development, the jury is still out. Biochim Biophys Acta 2010; 1822: 9–13.

    Article  Google Scholar 

  26. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We owe gratitude to Ian Tomlinson, Malcolm Dunlop and Richard Houlston (Oxford, UK) for critical appraisal of the data and manuscript.

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Author notes

  1. J Heijmans and N V J A Büller: These authors contributed equally to this work

Authors and Affiliations

  1. Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands

    J Heijmans, N V J A Büller, V Muncan & G R van den Brink

  2. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

    J Heijmans, N V J A Büller, E Hoff, A A Dihal, I Biemond, J C H Hardwick, D W Hommes, V Muncan & G R van den Brink

  3. Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands

    T van der Poll & M A D van Zoelen

  4. Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany

    A Bierhaus

  5. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands

    G R van den Brink

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  1. J Heijmans
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  2. N V J A Büller
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  3. E Hoff
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  8. I Biemond
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  10. D W Hommes
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Corresponding authors

Correspondence to J Heijmans or G R van den Brink.

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Heijmans, J., Büller, N., Hoff, E. et al. Rage signalling promotes intestinal tumourigenesis. Oncogene 32, 1202–1206 (2013). https://doi.org/10.1038/onc.2012.119

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