Hypoxia is often thought of as something cancer cells need to overcome to survive, necessitating the formation of new blood vessels to escape from areas of low oxygen. However, a growing body of evidence indicates that hypoxia might actually promote cancer development. Adding to this evidence, a recent study from Eileen White and colleagues shows that hypoxia drives cancer progression by promoting genomic instability, and that inactivation of apoptosis is essential for tumour-cell survival during this process.

The authors were interested in the role of the pro-apoptotic BCL2-family proteins BAK and BAX in tumorigenesis. In baby mouse kidney epithelial cells transformed with the adenoviral E1A oncogene and a dominant-negative form of p53, apoptosis is partially blocked — because of p53 inactivation — but the p53-independent apoptotic pathway that involves BAX and BAK is still functional. These cells are transformed in vitro, but do not form tumours when injected into animals, raising the question of why inactivation of the BAX/BAK apoptotic pathway is required for tumorigenesis.

White and colleagues investigated whether this is because these cells that express functional BAK and BAX are unable to survive in the hypoxic conditions that tumour cells encounter in vivo. Consistent with this, they found that the injected cells were subjected to high levels of hypoxia, resulting in cell death by apoptosis and necrosis. By contrast, despite being exposed to hypoxic conditions in vivo, cells in which the BAX/BAK pathway had been inactivated — either by deletion of Bax and Bak, or by overexpression of the anti-apoptotic protein BCL2 — survived to form tumours.

Interestingly, cells lacking BAX and BAK function formed giant polyploid tumour cells in vivo, whereas cells with functional BAX and BAK did not. This led White and colleagues to suggest that hypoxia promotes polyploidy, but that blocking the p53-independent apoptotic pathway is required for cells to survive this process.

To directly test whether inactivation of the BAX/BAK pathway is required for survival in hypoxic conditions, the authors used an in vitro ischaemia assay, in which cells are deprived of both oxygen and nutrients. Transformed cells expressing E1A and dominant-negative p53, but with functional BAK and BAX, underwent apoptosis in these conditions, whereas cells in which the BAK/BAX pathway was inactivated survived.

To test if this promoted genomic instability, the authors subjected cells to ischaemia, followed by a period of recovery, and looked at chromosome content and levels of apoptosis. Ischaemic conditions resulted in the generation of cells with increased chromosome content, regardless of the status of the BAX/BAK pathway. However, for cells in which this pathway was active, high levels of apoptosis were seen, and no polyploid cells were observed after the recovery period. By contrast, inactivation of BAX and BAK function led to the survival and persistance of polyploid cells.

Polyploidy is thought to be an important step in generating the genomic instability and aneuploidy that have been linked to tumour progression. So, it seems that by promoting this process, hypoxic and ischaemic conditions have a key role in cancer progression — but that loss or blockcade of the BAX and BAK pathway is required for survival during this step. This provides a new insight into the molecular changes that are needed for tumours to evolve, and might have important implications for therapeutic strategies that aim to kill cancer cells by inducing hypoxia.