RAGE signaling sustains inflammation and promotes tumor development
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RAGE signaling sustains inflammation and promotes tumor development. / Gebhardt, Christoffer; Riehl, Astrid; Durchdewald, Moritz; Németh, Julia; Fürstenberger, Gerhard; Müller-Decker, Karin; Enk, Alexander; Arnold, Bernd; Bierhaus, Angelika; Nawroth, Peter P; Hess, Jochen; Angel, Peter.
In: J EXP MED, Vol. 205, No. 2, 18.02.2008, p. 275-85.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - RAGE signaling sustains inflammation and promotes tumor development
AU - Gebhardt, Christoffer
AU - Riehl, Astrid
AU - Durchdewald, Moritz
AU - Németh, Julia
AU - Fürstenberger, Gerhard
AU - Müller-Decker, Karin
AU - Enk, Alexander
AU - Arnold, Bernd
AU - Bierhaus, Angelika
AU - Nawroth, Peter P
AU - Hess, Jochen
AU - Angel, Peter
PY - 2008/2/18
Y1 - 2008/2/18
N2 - 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.
AB - 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.
KW - 9,10-Dimethyl-1,2-benzanthracene
KW - Animals
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Inflammation
KW - Macrophage Inflammatory Proteins
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Receptor for Advanced Glycation End Products
KW - Receptors, Immunologic
KW - S100 Proteins
KW - Skin Neoplasms
KW - Tetradecanoylphorbol Acetate
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1084/jem.20070679
DO - 10.1084/jem.20070679
M3 - SCORING: Journal article
C2 - 18208974
VL - 205
SP - 275
EP - 285
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 2
ER -