RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.
Riehl et al. Cell Communication and Signaling 2009 7:12 doi:10.1186/1478-811X-7-12