S100 proteins and RAGE in cancer

RAGE, the receptor for advanced glycation endproducts, is a pattern recognition receptor that belongs to the immunoglobulin superfamily. In homeostasis, RAGE is expressed ubiquitously high only in the lung, and moderate to low in a wide range of cells such as endothelial cells, mononuclear phagocytes, smooth muscle cells, mesangial cells, and certain neurons. It is found either as a membrane-bound or soluble protein that is markedly and quickly upregulated by stress in both epithelial and inflammatory cells. RAGE binds multiple ligands, including advanced glycation end products (AGEs), amyloid fibrils, amphoterin, and various members of the S100 family of EF-hand calcium-binding proteins such as S100A4, S100A8/A9, S100A11, S100A12, and S100B. Activation and upregulation through a positive feedback loop of RAGE and, subsequently, perpetual RAGE S100 engagement effects the activation of diverse signaling cascades that initiate and stimulate chronic stress and survival pathways, depending on the distinct interacting S100 protein, environment, and developmental stage. This can result in chronic inflammation and is supposed a setting in which predominantly epithelial malignancies can arise. Therefore, exploring the function of RAGE and its panoply of S100 ligands in the setting of inflammation is critically important in understanding the role of this receptor in carcinogenesis and metastasis, but also in other pathological conditions such as radiation therapy-related vascular dysfunction. In this review, we summarize novel findings on RAGE S100 protein interaction and subsequently triggered signaling cascades from published reports and own ongoing studies. In particular, a comprehensive evaluation of S100 protein metabolism in rodent models using fluorine-18 radiolabeled recombinant S100 proteins and small animal positron emission tomography, further underlining the role of RAGE S100 protein interaction in normal and disease states in vivo, is demonstrated. These recent experiments also support the potential of RAGE and its S100 ligands as attractive theragnostic markers and targets, respectively.