Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer.

Hypoxia has been recognised as an important tumoral feature related to resistance to radiotherapy since 1933. Recent advances in biological research have revealed important aspects on the cellular response to hypoxic stimuli and on the role of hypoxia pathways in the metabolism, growth and progression of cancer. The hypoxia-inducible factors (HIF-1a and HIF-2a) have been identified as key proteins that directly respond to hypoxic stress. Following hypoxia, stabilisation and nuclear binding of HIFs triggers the expression of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. This review reports on and discusses the biology of the hypoxia pathways, the studies performed on the expression of HIFs in human cancer and the implications of hypoxia pathways in cancer therapy.