RAGE signaling sustains inflammation and promotes tumor development.
RAGE signaling sustains inflammation and promotes tumor development.
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DOI：
10.1084/jem.20070679
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发表时间：
2008-02-18
期刊：
影响因子：
--
通讯作者：
Angel P
中科院分区：
文献类型：
--
作者：
Gebhardt C;Riehl A;Durchdewald M;Németh J;Fürstenberger G;Müller-Decker K;Enk A;Arnold B;Bierhaus A;Nawroth PP;Hess J;Angel P
广泛的实验和临床证据强调了慢性炎症在促进肿瘤发展中的核心作用。然而，将短暂的炎症组织反应转化为促进肿瘤的微环境的分子机制在很大程度上仍然难以捉摸。我们发现，缺乏晚期糖基化终产物受体（RAGE）的小鼠对DMBA/ tpa诱导的皮肤癌具有抗性，并且在促进阶段表现出维持炎症的严重缺陷。因此，RAGE是tpa诱导的促炎介质上调、免疫细胞浸润维持和表皮增生所必需的。其潜在配体S100a8和S100a9的rage依赖性上调支持了S100/ rage驱动的前馈回路在慢性炎症和肿瘤促进中的存在。最后，骨髓嵌合体实验显示，RAGE在免疫细胞上的表达，而不是角化细胞或内皮细胞，是tpa诱导的真皮浸润和表皮增生所必需的。我们发现RAGE信号在肿瘤促进过程中驱动炎症反应的强度和维持，并为RAGE在连接慢性炎症和癌症中的新作用提供了直接的遗传证据。
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.
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