Article

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: 4.67). 06/2009; 7:12. DOI: 10.1186/1478-811X-7-12
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
137 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Advanced glycation endproducts (AGEs) are suspected to stimulate inflammatory signaling pathways in target tissues via activation of the receptor for AGEs. Endotoxins are generally recognized as potential contamination of AGE preparations and stimulate biological actions that are very similar as or identical to those induced by AGEs. In our study, we used glycolaldehyde-modified β-lactoglobulin preparations as model AGEs and employed two methods to remove endotoxin using either affinity columns or extraction with Triton X-114 (TX-114). Affinity column-purified AGEs retained their ability to stimulate inflammatory signaling as measured by mRNA expression of inflammatory cytokines in the human lung epithelial cell line Beas2b. However, glycolaldehyde-modified AGEs purified by extraction with TX-114 did not show any stimulation of mRNA expression of inflammatory cytokines. The presence of a cell stimulating endotoxin-like activity was demonstrated in the detergent phase after extraction with TX-114, thus indicating that not AGEs but a lipophilic contamination was responsible for the stimulation of inflammatory signaling. Our results demonstrate that glycolaldehyde-modified AGEs are unable to induce inflammatory signaling in receptor for AGE-expressing cells. The observed cell-activating activity can be ascribed to an endotoxin-like lipophilic contamination present in AGE preparations and affinity column purification was insufficient to remove this contamination.
    Molecular Nutrition & Food Research 02/2011; 55(2):291-9. DOI:10.1002/mnfr.201000140
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The function of the exocrine pancreas is the production and secretion of digestive enzymes. Major pathologies of the exocrine pancreas are pancreatitis, a sterile inflammation, and pancreatic adenocarcinoma, a highly lethal tumor. Both diseases involve cells of the immune system and calcium binding proteins of the S100 family. Here, we review the known function of these proteins in pancreatitis and pancreas cancer. Few S100 proteins were detected during pancreatitis and only for the S100A8/A9 complex data are available that eluci-date a presumable function. In a rodent model of caerulein-induced acute pancreatitis, pancreatic S100A8/A9 expression was exclusively detected in infiltrating leukocytes. S100A9 knockout animals developed less pancreatic tissue damage, no significant edema formation, and the intrapancreatic infiltration of leukocytes was inhibited. Purified S100A8/A9 dissoci-ated calcium-dependent cell-cell contacts between pancreatic acinar cells in vitro and in vivo. These results indicate that the dissociation of epithelial cell-cell contacts mediated by secreted S100A8/A9 is crucial for the infiltration of leukocytes into the pancreas. Several studies revealed an expression of S100 proteins in pancreatic cancers. Especially S100A8/A9 proteins were found in myeloid cells within tumor-associated stroma. Whether these proteins contribute to a recruitment of specific immune cells to tumors or to other steps of pancreatic tumor progression is not clear. None of the S100 proteins has been clearly confirmed as a pancrea tumor marker. Taken together, S100A8/A9 proteins are essential for the inflammation induced infiltration of leukocytes in murine pan-creatic tissue a mechanism which may also support tumor progression and metastasis.
    Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 01/2010; 8(4). DOI:10.2174/187152309789838984
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cells interact with the cells of the microenvironment not only by cell-cell-contacts but also by the release of signal substances. These substances are known to induce tumor vascularization, especially under hypoxic conditions, but are also supposed to provoke other processes such as tumor innervation and inflammatory conditions. Inflammation is mediated by two organ systems, the neuroendocrine system and the immune system. Therefore, we investigated the influence of substances released by PC-3 human prostate carcinoma cells on SH-SY5Y neuroblastoma cells as well as neutrophil granulocytes and cytotoxic T lymphocytes, especially with regard to their migratory activity. PC-3 cells express several cytokines and growth factors including vascular endothelial growth factors, fibroblast growth factors, interleukins and neurotrophic factors. SH-SY5Y cells are impaired in their migratory activity by PC-3 cell culture supernatant, but orientate chemotactically towards the source. Neutrophil granulocytes increase their locomotory activity only in response to cell culture supernantant of hypoxic but not of normoxic PC-3 cells. In contrast, cytotoxic T lymphocytes do not change their migratory activity in response to either culture supernatant, but increase their cytotoxicity, whereas supernatant of normoxic PC-3 cells leads to a stronger increase than that of hypoxic PC-3 cells. PC-3 cells release several signal substances that influence the behavior of the cells in the tumor's microenvironment, whereas no clear pattern towards proinflammatory or immunosuppressive conditions can be seen.
    Cell Communication and Signaling 07/2010; 8:17. DOI:10.1186/1478-811X-8-17

Preview (3 Sources)

Download
0 Downloads
Available from