title: RAGE signaling sustains inflammation and promotes tumor development.
abstract: 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.
authors.affiliation: Division of Signal Transduction and Growth Control, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Gebhardt
authors.forename: Astrid
authors.initials: A
authors.lastname: Riehl
authors.forename: Moritz
authors.initials: M
authors.lastname: Durchdewald
authors.forename: Julia
authors.initials: J
authors.lastname: Németh
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
authors.forename: Alexander
authors.initials: A
authors.lastname: Enk
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009418:S100 Proteins / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D019402:Macrophage Inflammatory Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate