Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours

Abstract

APOPTOSIS is a genetically encoded programme of cell death that can be activated under physiological conditions^1,2 and may be an important safeguard against tumour development^3–6. Regions of low oxygen (hypoxia) and necrosis are common features of solid tumours^7,8.Here we report that hypoxia induces apoptosis in oncogenically transformed cells and that further genetic alterations, such as loss of the p53 tumour-suppressor gene or over-expression of the apoptosis-inhibitor protein Bcl-2, substantially reduce hypoxia-induced cell death. Hypoxia also selects for cells with defects in apoptosis, because small numbers of transformed cells lacking p53 overtake similar cells expressing wild-type p53 when treated with hypoxia. Furthermore, highly apoptotic regions strongly correlate with hypoxic regions in transplanted tumours expressing wild-type p53, whereas little apoptosis occurs in hypoxic regions of p53-deficient tumours. We propose that hypoxia provides a physiological selective pressure in tumours for the expansion of variants that have lost their apoptotic potential, and in particular for cells acquiring p53mutations.