Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.
Graeber, Thomas G.; Osmanian, Cynthia; Jacks, Tyler; Housman, David E.; Koch, Cameron J.; Lowe, Scott W.; Giaccia, Amato J.
[Letter] Nature. 379(6560):88-91, January 4, 1996.

(Format: HTML)

APOPTOSIS is a genetically encoded programme of cell death that can be activated under physiological conditions *RF 1,2* and may be an important safeguard against tumour development *RF 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 p53 mutations.

(C) 1996 Macmillan Magazines Ltd.