Figure 2.

Schematic illustration of the functions of a receptor for advanced glycation end products (RAGE) in the cancer microenvironment: (A) binding of RAGE and its ligands promotes angiogenesis and cancer development by upregulating PKI3/mTOR/Akt, MAPKs, MMPs, VEGF, NF-κB, and downregulating p53 signaling; (B) secretion of HMGB1 from inflamed or injured cells followed by its binding with RAGE results in the increased release of proinflammatory cytokines via NF-κB activation and ensuing harmful inflammatory responses; (C) HMGB1 operates via NF-κB and epigenetic pathways in the cancer microenvironment to exert its long-lasting effects on surviving tumor cells, immune cells, and stromal cells. Together with STAT3, NF-κB controls genes that promote metastasis, angiogenesis, and cancer development; (D) upregulation of VEGF leads to angiogenesis resulting in cancer progression; and (E) increased expression of MMPs and MMPKs promotes metastasis in various cancers.