RAGE signaling sustains inflammation and promotes tumor development.
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.
Gebhardt
Christoffer
C
Division of Signal Transduction and Growth Control, German Cancer Research Center, 69120 Heidelberg, Germany.
Riehl
Astrid
A
Durchdewald
Moritz
M
Németh
Julia
J
Fürstenberger
Gerhard
G
Müller-Decker
Karin
K
Enk
Alexander
A
Arnold
Bernd
B
Bierhaus
Angelika
A
Nawroth
Peter P
PP
Hess
Jochen
J
Angel
Peter
P
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
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