Macrophage infiltration and angiogenesis in human malignancy

Novartis Found Symp. 2004;256:189-200; discussion 200-4, 259-69.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • DNA-Binding Proteins / physiology
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Macrophage Activation
  • Macrophages / physiology*
  • Neoplasms / blood supply*
  • Neoplasms / immunology
  • Neovascularization, Pathologic*
  • Nuclear Proteins / physiology
  • Transcription Factors*

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors