RAGE signaling sustains inflammation and promotes tumor development

J Exp Med. 2008 Feb 18;205(2):275-85. doi: 10.1084/jem.20070679. Epub 2008 Jan 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Female
  • Gene Expression Regulation, Neoplastic
  • Inflammation / chemically induced
  • Inflammation / immunology*
  • Inflammation / pathology
  • Macrophage Inflammatory Proteins / genetics
  • Macrophage Inflammatory Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology*
  • S100 Proteins / genetics
  • S100 Proteins / immunology*
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • Tetradecanoylphorbol Acetate

Substances

  • Macrophage Inflammatory Proteins
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100 Proteins
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate