title: Macrophage infiltration and angiogenesis in human malignancy.
abstract: 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.
authors.affiliation: Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, Oxford OX3 9DU, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Knowles
authors.forename: Russell
authors.initials: R
authors.lastname: Leek
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000502:physiology; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors