Macrophage infiltration and angiogenesis in human malignancy.

It is well recognized that human tumours are hypoxic compared to normal adjacent tissues and that hypoxia is related to a poor outcome regardless of modality of treatment, including surgery alone, radiotherapy or chemotherapy. Hypoxia regulates a complex programme of gene transcription via hypoxia-inducible factors 1 and 2 (HIF-1, -2). We have shown that in breast cancer and many other tumour types, tumour-associated macrophages express high levels of HIF-2alpha compared to normal tissue macrophages and compared to the tumour. This high macrophage HIF-2alpha is an independent prognostic factor for poor outcome. The mechanisms up-regulating HLF-2alpha in macrophages may include inflammatory cytokines as well as hypoxia. Differentiation of monocytes into macrophages increases the basal level of HIF-2alpha protein and changes the programme of hypoxia. Many of these inducible genes are involved in inflammation and angiogenesis. Thus, the conversion of a peripheral monocyte into a macrophage generates a complex new programme of hypoxia-responsive genes that may contribute to angiogenesis and the complex microenvironment within the tumour, and as such provides important targets for therapy.