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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Available from: Thiruvengadam Arumugam, Feb 25, 2015
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    • "RAGE has been overexpressed in the brain, breast, colon, colorectal, lung, prostate, oral squamous cell, and ovarian cancers, in addition to lymphoma and melanoma[41]this clarifies the direct relationship between RAGE and cancer cell proliferation, survival, migration, and invasion of tumor cells[42]. Targeted knockdown of RAGE in the tumor cell, leads to increased apoptosis. "

    Full-text · Article · Jan 2016
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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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    • "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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    ABSTRACT: The two main reasons for death of cancer patients, tumor recurrence and metastasis, are multi-stage cellular processes that involve increased cell plasticity and coincide with elevated resistance to anti-cancer treatments. Epithelial-to-mesenchymal transition (EMT) is a key contributor to metastasis in many cancer types, including thyroid cancer and is known to confer stem cell-like properties onto cancer cells. This review provides an overview of molecular mechanisms and factors known to contribute to cancer cell plasticity and capable of enhancing cancer cell resistance to radio- and chemotherapy. We elucidate the role of DNA repair mechanisms in contributing to therapeutic resistance, with a special emphasis on thyroid cancer. Next, we explore the emerging roles of autophagy and damage-associated molecular pattern responses in EMT and chemoresistance in tumor cells. Finally, we demonstrate how cancer cells, including thyroid cancer cells, can highjack the oncofetal nucleoprotein high-mobility group A2 to gain increased transformative cell plasticity, prevent apoptosis, and enhance metastasis of chemoresistant tumor cells.
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