Receptor for Advanced Glycation End Products (RAGE) Ligand Axis as a Mediator of Inflammation and Oxidative Stress in Cancer: Implications for Cancer Progression and Therapeutic Targeting.

The Receptor for Advanced Glycation End Products (RAGEs) is a cell surface immunoglobulin class of molecules. RAGE is also recognized as a Pattern Recognition Receptor (PRR), which influences innate immune responses. RAGE also influences adaptive immune responses. The promoter of the RAGE gene can bind to proinflammatory transcription factors such as NF-κB, which activate RAGE transcription and subsequent expression. Once expressed, RAGE interacts with seemingly unrelated ligands, such as AGE, HMGB1, S100, and others, and the RAGE-ligand(s) axis triggers inflammation and oxidative stress and sustains a vicious cycle of self-propagation. Exposure to inflammatory and oxidative stress responses is a hallmark of complications in different cancers, including their proliferation, survival, angiogenesis, invasion, metastasis, and apoptosis. In the tumor immune microenvironment, the RAGE-ligand(s) axis inhibits antitumor immunity by activating Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs/M2 macrophages) and by suppressing tumor suppressor proteins such as p53 and PTEN. Paradoxically, under normal physiological conditions, high RAGE expression in lung tissues protects this organ from cancer initiation. Multiple factors, including the diverse functions of RAGE splice variants, may influence lung-specific RAGE expression and activity. This comprehensive review illustrates the various mechanisms through which the RAGE-ligand(s) axis promotes the development of multiple cancers, including lung cancer, highlighting the role of inflammation generated by RAGE-ligand(s) interactions in the progression of different cancers. In addition, the therapeutic relevance of targeting the RAGE-ligand axis and highlights emerging strategies to modulate pathological RAGE signaling in cancer is discussed.