© 2007 American Thoracic Society doi: 10.1164/rccm.200610-1470ED
RAGE in Lung TumorsUniversity of Colorado Health Sciences Center, Denver, Colorado The discovery of a complicated and medically relevant signaling pathway that is based on advanced glycation end products (AGE) has created new interest in unprogrammed post-translational changes that may be affected by environmental conditions. AGE are formed by nonenzymatic covalent reactions between sugars and the amino groups of proteins and lipids (reviewed in References 1 and 2). They are formed over a period of weeks and, once formed, are highly stable. Their formation is enhanced by hyperglycemia, inflammation, and oxidative stress. In the extracellular matrix, AGE stiffen and stabilize aberrant or inappropriately deposited proteins, including basement membrane and amyloid. Increased levels of AGE have been described in the lens and vascular tissue of diabetic smokers in comparison to nonsmokers, suggesting that smoking enhances the formation of AGE (3).
Fifteen years ago, AGE were found to associate with the multiligand transmembrane receptor for AGE (RAGE) (4, 5), a member of the immunoglobulin superfamily. Binding of AGE to RAGE causes cellular activation, resulting in enhanced expression of cytokines and growth factors, increased cell migration, and activation of the transcription factor nuclear factor- A further twist to the story of RAGE function was added with the discovery of a stable splice variant of RAGE, called the endogenous secretory RAGE (esRAGE) (11). This variant is shortened and contains a unique sequence in its cytoplasmic domain with the consequence that transduction of signals from surface receptor through a cytoplasmic signaling cascade is abolished. esRAGE is therefore thought to function as a decoy receptor, protecting the cell from the effects induced by activation of a full-length receptor. In this issue of the Journal (pp. 184–189), Kobayashi and colleagues report that expression of esRAGE was reduced or absent in 75% of non–small cell lung cancers (12). If the effect of esRAGE is to act as a decoy receptor and to block activation that might occur through full-length RAGE, one would expect that tumors with high levels of esRAGE might have lower levels of full-length RAGE, lower invasiveness, and improved survival. This proves to be at least partially true. No consistent relationship between the expression levels of esRAGE and full-length RAGE could be found by immunohistochemistry. However, in at least some cases, there was a reciprocal relationship between esRAGE and the full-length form of receptor. In gene transfer experiments, cell lines transfected with esRAGE had pronounced reduction in proliferative activity (p < 0.05) and an accumulation of cells in the G0/G1 phase of the cell cycle. Finally, esRAGE expression as determined by an immunohistochemical test performed on 182 tumors was an independent predictor of survival. Several questions remain unanswered. The first relates to whether these results relating to the role of esRAGE can be confirmed. Immunohistochemical testing has the virtue that it can be rapidly applied to clinical samples and is relatively simple to perform. However, the results with immunohistochemistry are semiquantitative at best, and should be confirmed by more quantitative methods. Kobayashi and colleagues were able to assess 36 tumors by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR). While qRT-PCR results were similar to those with immunohistochemical assays, the number of cases evaluated was not sufficient to confirm the predictive value of esRAGE expression as suggested by the findings with immunohistochemistry. A second question would be the nature of the ligand for esRAGE and RAGE in those cases where full-length RAGE is expressed. Suggested candidates have included amphoterin, S100/calgranulin, and matrix metalloproteinases (6). How expression of a specific ligand relates to the activation of RAGE and the interactions between RAGE and its decoy esRAGE is yet to be determined. Finally, this experiment of nature suggests that endogenous changes in tumor cells, resulting in receptor substitution, can regulate signaling in tumor cells. Can this internal signaling be mimicked or enhanced by therapeutic interventions? If the answer to the question is "yes," then esRAGE could become the rage of pulmonary oncology. FOOTNOTES Conflict of Interest Statement: W.A.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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