The receptor RAGE: Bridging inflammation and cancer

German Cancer Research Center, DKFZ-ZMBH Alliance, Division of Signal Transduction and Growth Control (A100), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. .
Cell Communication and Signaling (Impact Factor: 3.38). 06/2009; 7(1):12. DOI: 10.1186/1478-811X-7-12
Source: PubMed


The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

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    • "RAGE is thought to be important in a variety of pathological conditions and is implicated in chronic inflammatory processes present in diabetes [61], rheumatoid arthritis [62], and Alzheimer's disease [63]. RAGE regulates inflammation though NF-κB, AP-1, and Stat3 transcriptional regulation [64]. Biochemical and genetic studies have found that the IKK complex plays a critical role in the activation of NF-κB. "
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    ABSTRACT: High mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE), which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia ( P. intermedia ) lipopolysaccharide (LPS) on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1). RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF- κ B activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection.
    Full-text · Article · Jul 2014 · Mediators of Inflammation
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    • "For instance, in colon, gastric, breast, pancreatic and liver cancer tissues RAGE is found up-regulated and suppression of RAGE expression or RAGE signaling reduces cellular proliferation and/or migration [12] [13] [14] [15] [16] [17]. However, in lung carcinomas and rhabdomyosarcoma, it is the down-regulation of RAGE that results in increased cellular proliferation and/or migration [18] [19], suggesting that the role of RAGE is cancer specific and depends of the tissue and tumor environment [20] [21] [22]. "
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    ABSTRACT: The formation of melanoma metastases from primary tumor cells is a complex phenomenon that involves the regulation of multiple genes. We have previously shown that the receptor for advanced glycation end products (RAGE) was up-regulated in late metastatic stages of melanoma patient samples and we hypothesized that up-regulation of RAGE in cells forming a primary melanoma tumor could contribute to the metastatic switch of these cells. To test our hypothesis, we overexpressed RAGE in the WM115 human melanoma cell line that was established from a primary melanoma tumor of a patient. We show here that overexpression of RAGE in these cells is associated with mesenchymal-like morphologies of the cells. These cells demonstrate higher migration abilities and reduced proliferation properties, suggesting that the cells have switched to a metastatic phenotype. At the molecular level, we show that RAGE overexpression is associated with the up-regulation of the RAGE ligand S100B and the down-regulation of p53, ERK1/2, cyclin E and NF-kB. Our study supports a role of RAGE in the metastatic switch of melanoma cells.
    Preview · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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    • "These proteins are directly involved in piloting metastases by the ligation of TLR4 and RAGE receptors [29,30,44]. The latter receptor, critical to bridging inflammation and cancer [45], and its ligation, initiates a feed-forward loop that potentiates inflammation, but may also favor the oncogenic switch [24,30]. In agreement with the hypothesis that S100A8 and S100A9 have a potential metastatic role, S100A8 and S100A9 mRNA levels were almost undetectable in the primary BxPC3, MiaPaCa2 and Panc1, while they were highly expressed by the metastatic SUIT2 and Capan1 PDAC cell lines [46]. "
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    ABSTRACT: In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFbeta1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-kappaB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-kappaB, Akt and mTOR signaling with S100A8, but mainly with TGFbeta1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-kappaB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-kappaB and Akt in the presence of an intact TGFbeta1 canonical signaling pathway. TGFbeta1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFbeta1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFbeta1 (MALDI-TOF/MS and co-immuno-precipitation). The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFbeta1 on cell signaling, and the formation of complexes between TGFbeta1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.
    Full-text · Article · Mar 2014 · Cell Communication and Signaling
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