Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Abstract

This Review discusses four important and interrelated features of tumour hypoxia: the hypoxic response, the factors that influence tumour hypoxia, the role of hypoxia in the initiation of angiogenesis (angiogenic switch) and how hypoxia influences treatment responses. The hypoxia response, driven primarily by the heterodimeric transcription factor hypoxia-inducible factor 1 (HIF1) influences cell survival, behaviour and angiogenesis. Several pathophysiological factors contribute to the development of tumour hypoxia, which is typified by heterogeneity in oxygenation in space and in time. Conflicting theories exist with respect to whether hypoxic stabilization of HIF1 is the primary feature of the angiogenic switch. There is clear evidence that HIF1 upregulation is associated with angiogenesis acceleration as opposed to angiogenesis initiation. The appearance of perivascular (oxygenated regions) HIF1 expression during angiogenesis acceleration might be the result of increased levels of reactive oxygen species, associated with proliferation and/or instability in flow and hypoxia–reoxygenation injury. Cytotoxic therapies, such as radiation therapy, improve tumour oxygenation but also increase HIF1 levels and transactivation of target genes through mechanisms associated with stress granule depolymerization and the production of free radicals. The upregulation of HIF1 in these circumstances protects tumour and endothelial cells from damage by the cytotoxic therapy.