Figure 2.

Hypoxia induces marked changes in the phenotype of macrophages. Macrophages upregulate hypoxia-inducible transcription factor (HIF)-1 and HIF-2 in hypoxia, which translocate to the nucleus to induce the expression of a wide array of target genes. Several important cell-surface receptors are upregulated in hypoxia, including the glucose receptor GLUT-1 (for increased glucose uptake as the cell switches to anaerobic glycolysis to make ATP in the absence of oxygen), the chemokine stromal cell-derived factor-1 (SDF-1) receptor CXCR4, and the angiopoietin receptor Tie-2. Hypoxia also stimulates the expression of a wide array of other pro-tumour cytokines, enzymes and receptors, grouped here according to their known function in tumours. Downregulation of a factor or tumour-associated macrophage function is indicated by an arrow [15, 17, 18]. Ag, antigen; COX, cyclo-oxygenase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PGE2, prostaglandin E₂; TF, tissue factor; uPA/R, urokinase plasminogen activator receptor; VEGF, vascular endothelial growth factor.