RAGE signaling sustains inflammation and promotes tumor development

• DOI: 10.1084/jem.20070679
• Publication Date: 2008-01-22T01:35:11Z
• Authors: Christoffer Gebhardt; Astrid Riehl; Moritz Durchdewald; Julia Németh; Gerhard Fürstenb...; Karin Müller-Decker; Alexander Enk; Bernd Arnold; Angelika Bierhaus; Peter P. Nawroth; Jochen Hess; Peter Angel
• Keywords: Inflammation; Mice, Knockout; 0303 health sciences; Skin Neoplasms; 9,10-Dimethyl-1,2-benzanthracene; Receptor for Advanced Glycation End Products; S100 Proteins; Macrophage Inflammatory Proteins; 12. Responsible consumption; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Brief Definitive Reports; Animals; Tetradecanoylphorbol Acetate; Female; Receptors, Immunologic

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.