Molecular mechanisms underlying tumorigenesis reflect a complex mesh of processes promoting unchecked cellular proliferation, invasion, induction of neovessel formation, and means of evading the immune response. The Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily first identified as a cell surface interaction site for the products of nonenzymatic glycoxidation of proteins, the Advanced Glycation Endproducts, or AGEs. Recent studies indicated a putative natural function for RAGE; in developing neurons of the central nervous system, upregulation of RAGE and its ligand amphoterin occurs, especially at the leading edge of advancing neurites. In vitro, amphoterin-RAGE interaction mediates outgrowth of cerebral cortical neurites, as the process is inhibited by blocking antibodies to RAGE, or soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE. These findings, along with the observation that enhanced levels of amphoterin and RAGE are present in tumors, suggested their possible contribution to tumor biology. In murine tumor models, blockade of amphoterin/RAGE suppresses activation of members of the kinase family, p44/p42, p38 and SAPKIJNK involved in modulating tumor proliferation, invasion/migration, and activation of matrix metalloproteinases (MMPs). In vivo, blockade of RAGE-amphoterin suppressed primary tumors grown from implanted rat C6 glioma, and lung metastases in mice bearing Lewis lung carcinoma. Blockade of RAGE suppressed tumor cell proliferation in vivo. Histologic analysis revealed that in mice in whom access to RAGE was suppressed by genetically-modulated expression of soluble RAGE by C6 glioma, or its function in C6 glioma was imp4ired by introduction of a dominant negative form of RAGE, a striking decrease in tumor invasion, migration and activity of MMP2 and 9 was evident compared with mice bearing C6 glioma and functionally-active RAGE. We thus speculate that amphoterin-RAGE modulates critical properties within the tumor bed and hypothesize that subsequent to activation of tumor RAGE by ligand such as amphoterin, key cell signalling pathways are activated that contribute to tumor pro! jferation, invasion, migration and degradation of extracellular matrix. We propose to delineate the signal transduction pathways activated upon engagement of RAGE that enhance cellular proliferation and invasiveness, and to delineate the mechanisms by which blockade of RAGE suppresses tumor proliferation, as a means to determine if blockade of RAGE might arrest progression of pre-malignant lesions into carcinoma.
| Hudson, Barry I; Kalea, Anastasia Z; Del Mar Arriero, Maria et al. (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283:34457-68 |
| Fuentes, Maren K; Nigavekar, Shraddha S; Arumugam, Thiruvengadam et al. (2007) RAGE activation by S100P in colon cancer stimulates growth, migration, and cell signaling pathways. Dis Colon Rectum 50:1230-40 |
| Huang, Emina H; Park, Juliet C; Appelman, Henry et al. (2006) Induction of inflammatory bowel disease accelerates adenoma formation in Min +/- mice. Surgery 139:782-8 |
