The Journal of Experimental Medicine
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Published online January 21, 2008
doi:10.1084/jem.20070679
The Journal of Experimental Medicine, Vol. 205, No. 2, 275-285
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Gebhardt et al.
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BRIEF DEFINITIVE REPORT

 RAGE signaling sustains inflammation and promotes tumor development

Christoffer Gebhardt1,4, Astrid Riehl1, Moritz Durchdewald1, Julia Németh1, Gerhard Fürstenberger2, Karin Müller-Decker2, Alexander Enk4, Bernd Arnold3, Angelika Bierhaus5, Peter P. Nawroth5, Jochen Hess1, and Peter Angel1

1 Division of Signal Transduction and Growth Control, 2 Research Group Eicosanoids and Tumor Development, and 3 Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany
4 Department of Dermatology, University Hospital Heidelberg, 69115 Heidelberg, Germany
5 Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, 69120 Heidelberg, Germany

CORRESPONDENCE Peter Angel: p.angel{at}dkfz.de

A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer.

P. Angel and J. Hess contributed equally to this work.


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