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 and may be an important safeguard against tumour development. Regions of low oxygen (hypoxia) and necrosis are common features of solid tumours. 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 overexpression 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.

Role of redox potential and reactive oxygen species in stress signaling

“…The role of ROS in p53-mediated apoptosis has been demonstrated (Johnson et al, 1996). Furthermore, an increased tumor cells capacity for undergoing apoptosis in response to ROS was also shown to be p53-dependent (Graeber et al, 1996). This is consistent with the increased radio sensitivity that has been associated with oxidative signaling in repair de®cient syndromes, such as ataxia telangiectasia (Lavin, 1998).…”

Mdm2: keeping p53 under control

“…The main tumor suppressor protein targetted by Mdm2, p53, is known to be mutated in more than 50% of human tumors (Hollstein et al, 1991) and is a key element in the protection against tumor development. The role of p53 in the DNA damage checkpoint is now clearly established (Kastan et al, 1991), and recent results also implicate the protein in the spindle formation checkpoint and in the response to depletion of oxygen or ribonucleotides (Minn et al, 1996;Graeber et al, 1996;Linke et al, 1996). Activation of p53 by DNA damage or other stresses leads to cell cycle arrest or to apoptosis.…”

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

“…A short-term hypoxia followed by reoxygenation transiently enhances invasive and metastatic potential of some tumor cells (Young and Hill, 1990;Graham et al, 1999;Cairns et al, 2001). Tumor hypoxia selects p53 À/À transformed cells and thereby expands cells with diminished apoptotic potential in vitro (Graeber et al, 1996). These mechanisms all together are likely to influence the malignant progression of tumor cells (Hill, 1990;Russo et al, 1995;Graeber et al, 1996;Coquelle et al, 1998;Dachs and Chaplin, 1998).…”

“…Tumor hypoxia selects p53 À/À transformed cells and thereby expands cells with diminished apoptotic potential in vitro (Graeber et al, 1996). These mechanisms all together are likely to influence the malignant progression of tumor cells (Hill, 1990;Russo et al, 1995;Graeber et al, 1996;Coquelle et al, 1998;Dachs and Chaplin, 1998). Besides, since hypoxic tumor cells cease to divide, they are resistant to conventional radiotherapy and chemotherapy (Rice et al, 1986;Young and Hill, 1990;Teicher, 1994).…”