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.

Deciphering RAGE signalling for clinical interventions. RAGE is known to interact with a broad spectrum of extracellular ligands and multiple signal transduction pathways have been shown to be directly (solid line) or indirectly (dotted line) activated upon RAGE ligation. Several tools for interference with RAGE-mediated signalling have been described: sRAGE, RAGE blocking antibodies and a small molecule inhibitor [21]. However, their successful use in clinical applications demands a comprehensive knowledge on intracellular signalling pathways and gene regulatory networks. So far, the unstructured C-terminal part of RAGE has hampered many approaches to find direct interaction partners within the cytosol (A). Other signalling molecules (B) besides PI3K, different MAPKs, Rho GTPases and ROS might be involved in functions of RAGE. On the level of transcriptional regulation, NF-κB, AP-1 and Stat3 have emerged as crucial targets of RAGE signalling, nevertheless other transcription factors (C) might be involved in regulation and function of RAGE as well. Finally, unravelling the RAGE-regulated genetic programme (D) will provide insight to the functional output of RAGE signalling. Cdc42, cell division cycle 42; Erk1/2, extracellular signal-regulated kinase 1/2; IκB, inhibitor of kappa B; IKK, inhibitor of kappa B kinase; JAK, Janus kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated kinase; MKK, mitogen-activated kinase kinase; NF-κB, nuclear factor kappa B; PI3K, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; ROS, reactive oxygen species; Stat3, signal transducer and activator of transcription.