Fig. 1.

Cellular events and signalling elements involved in the regulation of the stabilization and activation of hypoxia-inducible factors. The increase in the stability and activation of HIFs, HIF-1α and HIF-2α, in cancer cells including cancer stem/progenitor cells, which may be induced via different growth factor and cytokine pathways under normoxic and hypoxic conditions, hypoxic microenvironment and inflammation are illustrated. The potential cellular signalling elements modulated through the up-regulation of HIFs and which can contribute to high self-renewal, altered glycolytic metabolism, invasion, metastases, treatment resistance and disease relapse are also indicated. BCRP/ABCG2: breast cancer resistance protein; CAIX: carbonic anhydrase; EGFR: epidermal growth factor receptor; GLUT: glucose transporter; IL-6: interleukin-6; MAPK: mitogen-activated protein kinase; MCT-4: monocarboxylate transporter-4; MIC-1: macrophage inhibitory cytokine-1; MMPs: metalloproteinases; mTOR: molecular target of rapamycin; NF-κB: nuclear factor-κB; RTK: receptor tyrosine kinase; PI3K: phosphatidylinositol 3′-kinase; PGK1: phosphoglycerate kinase 1; PKM: pyruvate kinase M; P-gp: P-glycoprotein; ROS: reactive oxygen species; TGF-β: transforming growth factor-β; TNF-α: tumour necrosis factor-α; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor.