RAGE and RAGE ligands in cancer

Department of Cancer Biology, The University of Texas. Anderson Cancer Center, Unit 953, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
Current Molecular Medicine (Impact Factor: 3.62). 01/2008; 7(8):777-89. DOI: 10.2174/156652407783220697
Source: PubMed


The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor with multiple ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's disease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which include the S100/calgranulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors. These ligands can interact in an autocrine manner to directly activate cancer cells and stimulate proliferation, invasion, chemoresistance, and metastasis. RAGE ligands derived from cancer cells can also influence a variety of important cell types within the tumor microenvironment, including fibroblasts, leukocytes, and vascular cells, leading to increased fibrosis, inflammation, and angiogenesis. Several of the cells in the tumor microenvironment also produce RAGE ligands. Most of the cancer-promoting effects of RAGE ligands are the result of their interaction with RAGE. However, these ligands also often have separate intracellular roles, and some may interact with other extracellular targets, so it is not currently possible to assign all of their effects to RAGE activation. Despite these complications, the bulk of the evidence supports the premise that the ligand-RAGE axis is an important target for therapeutic intervention in cancer.

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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.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 07/2014; 1842(7). DOI:10.1016/j.bbadis.2014.02.013 · 4.88 Impact Factor
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    • "Receptor for advanced glycation end product belongs to the immunoglobulin-like family of transmembrane receptors (88, 93) and is expressed in several human cancers (94). The three extracellular domains of RAGE, the V-, C1-, and C2-domain, function in ligand binding (93). "
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    Frontiers in Endocrinology 03/2014; 5:37. DOI:10.3389/fendo.2014.00037
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    • "RAGE appears to be involved in many different disease states, including cancer [6], retinal disease [7], atherosclerosis and cardiovascular disease [8], Alzheimer’s disease [9], respiratory disorders [10], liver disease [11], and diabetic nephropathy [12]. Mice lacking RAGE are viable and apparently healthy, and appear to be resistant to many of the disease states listed above [13] [14]. "
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    ABSTRACT: The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels.
    PLoS ONE 01/2014; 9(1):e86903. DOI:10.1371/journal.pone.0086903 · 3.23 Impact Factor
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