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The Role of the Receptor for Advanced Glycation End Products in Malignant Melanoma
Introduction
Melanoma is a disease of melanocytes, the cells of our skin that produce melanin. Because abnormal growth of melanocytes can be readily followed by visual observation of the skin, early stage melanoma tumors can be easily detected and after surgical resection, patients have a very good prognosis with a 5-year survival of 80–100%. However, once melanoma cells escape the primary tumor and form metastases, the survival rate of patients decreases dramatically with a 10-year survival of less than 10% ( ). For more than 30 years, the gold standard for treatment of melanoma consisted of the alkylating agent dacarbazine, however, the response rates were low and the survival benefits minimal ( ). Since 2011, several new drugs have been approved by the FDA for the treatment of metastatic melanoma ( ). Two drugs, vemurafenib and dabrafenib, are small molecules that target the BRAF enzyme if the enzyme has the V600E mutation, the most frequent mutation of BRAF found in melanoma tumors ( ). Although treatment with the BRAF inhibitors resulted in promising response rates, most patients experience regrowth of drug-resistant tumors within a year of treatment, due to the reactivation of the MEK signaling pathway. To overcome this problem of drug resistance, new combination therapies have been tested in clinical trials ( ). One combination consists of dabrafenib with trametinib, an inhibitor of MEK ( ). Several monoclonal antibodies have also been recently approved for the treatment of metastatic melanoma ( ). Ipilimumab targets the cytotoxic T-lymphocyte antigen-4 receptor at the surface of T cells, resulting in suppression of T-cell inhibition ( ). Nivolumab and pembrolizumab target the program cell death (PD1) receptor on the surface of T-cells, therefore releasing PD-1-mediated inhibition of the immune response, and resulting in enhanced antitumor immune responses ( ). Because of their mechanisms of action, these monoclonal antibodies can generate life threatening immune-related adverse events in patients ( ). In addition, because of the nature of the target cells, the therapeutic efficacy of these antibodies depends on the levels of infiltrated immune cells in the melanoma tumors.
Despite these recent advances in melanoma therapy, it is important to continue searching for novel therapeutic strategies and targets. Recent studies have suggested that the receptor for advanced glycation end products (RAGE) should be evaluated as a therapeutic target in melanoma ( ). We will discuss here evidence supporting a role of RAGE and its ligands in the progression of melanoma.
Biology of the Receptor for Advanced Glycation End Products
Physiological Role of RAGE
RAGE was initially identified as a receptor for advanced glycation end products. Staining for RAGE showed that this receptor is most abundantly expressed in skeletal muscle, lung, and heart. Studies of RAGE knock-out animals revealed that RAGE is not essential for life but that it has a role in innate immunity, peripheral nerve repair, and shows protective effects in the lungs ( ). Behavioral studies showed no changes in spatial memory or anxiety in RAGE knock-out animals and only increased cage activity and sensitivity to auditory stimuli.
Whereas the physiological role of RAGE needs to be further investigated, stronger evidence supports the role of RAGE in multiple diseases. For example, studies have shown that RAGE is involved in complications of diabetes, in Alzheimer’s disease, in infectious diseases, and in multiple cancers, including melanoma ( ).
RAGE Structure and Isoforms
RAGE belongs to the superfamily of immunoglobulin (Ig)-like receptors. It consists of a single transmembrane domain, a large Ig-like extracellular domain and a relatively short intracellular domain ( Fig. 8.1 ) ( ). The extracellular part is the site of interaction with RAGE ligands: it comprises an Ig-like variable (V) domain (residues 23–119) and two Ig-like constant domains (C1: residues 120–233 and C2: residues 234–325) ( Fig. 8.1 ) ( ). Recent studies suggest that RAGE exists as dimers at the surface of cells. However, it is currently not exactly known how the different domains of the receptor interact with each other or with RAGE ligands during signal transduction ( ). Several structural models have recently been proposed, suggesting interactions between RAGE V domains, C1 domain or C2 domain ( ). It has been hypothesized that RAGE recognizes similar structural elements or patterns within its numerous ligands and therefore RAGE has been classified as a pattern recognition receptor.
The main form of RAGE is the full-length form described in Fig. 8.1 . However, several spliced and proteolytically produced isoforms have been described. The most common isoform of RAGE, besides the full-length RAGE, is the soluble form or sRAGE. sRAGE lacks both the intracellular and transmembrane domains. sRAGE can result either from a splicing event or from the action of a metalloprotease such as ADAM 10 ( ).
sRAGE has been suggested to interact with circulating RAGE ligands and to suppress RAGE signaling by acting as decoy receptor. However, this role for sRAGE is controversial because of the low levels of circulating sRAGE (picomolar) compared to the 1000-fold higher levels of RAGE ligands (nanomolar) ( ). Recently, the group of Fritz proposed a more attractive role for sRAGE. They suggested that one molecule of sRAGE could form a hetero-complex with one molecule of full-length RAGE, resulting in a nonfunctional RAGE dimer ( ).
Although the role of sRAGE is not fully understood, studies have shown that in certain pathologies, the levels of sRAGE could serve as a biomarker for the progression of the disease. For example, lower levels of sRAGE have been reported in Alzheimer’s patients, or patients with certain cancers compared to healthy control individuals. However, in other diseases such as diabetes, the levels of sRAGE does not always correlate with the disease progression (reviewed and discussed in ). Other splicing isoforms, such as the one lacking the N-terminal V domain, have been reported but their physiological functions are still not fully understood ( ).
RAGE Signaling
RAGE signaling is complex and the engagement of RAGE by its ligands can result in ligand specific and cell-type specific signaling. Fig. 8.1 illustrates several important kinases (PI3K, AKT, ERK1/2 and JAK), GTPases (Ras), and transcription factors (NF-κB, AP-1, and STAT3) that have been found activated in RAGE dependent manner ( ). In addition, RAGE activation by its ligands often results in the upregulation of the receptor itself, resulting in positive feedback loops ( Fig. 8.1 ).
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