Published online 31 July 2010 | Nature | doi:10.1038/news.2010.383


Cellular suicide spurs cancer

New role for protein 'suicide switch' in aiding and abetting cancer.

DNA and p53The protein p53 is a key player in the process driving cell death.Thomas Splettstoesser

To prevent cancer, it turns out, cellular suicide is not the answer. Although genetically programmed suicide switches are key to clearing out damaged cells before they can form tumours, studies in mice have found that cell death can sometimes clear the way for cancer to grow.

The results, if confirmed in humans, could have implications for cancer therapies now under development: some that aim to stimulate programmed cell death could actually stimulate cancer as well.

Two studies published today in the journal Genes & Development1,2 look at the role of a protein called PUMA, which triggers cell death in response to damaged DNA. PUMA is activated by the well-known tumour-suppressor protein p53, sometimes called 'the guardian of the genome'.

More than half of all human tumours carry mutations in p53. Mice that lack p53 are riddled with cancer, and typically succumb to the disease within three months. "You can read it in any textbook," says Andreas Villunger, a molecular biologist at Innsbruck Medical University in Austria and a co-author of one of the papers1. "The death of cells that have undergone DNA damage is critical to cancer prevention."

Without PUMA, p53 can't flip the cell-suicide switch. With this in mind, Villunger and his colleagues generated mice that lack the PUMA protein and then subjected those mice to DNA-damaging radiation. The researchers expected the animals to quickly develop cancer and die.

Instead, the mice that lacked PUMA fared better than normal laboratory mice. "We were waiting for the mice to develop tumours and it just didn't happen," says Villunger.

A separate research team headed by Andreas Strasser of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, observed the same phenomenon: the absence of the suicide switch had protected the mice, not harmed them2.

The results are exciting and unexpected, says Lin Zhang of the University of Pittsburgh Cancer Institute in Pennsylvania, who was not involved in the work. What's more, the finding has implications for a class of anticancer drugs designed to mimic PUMA, he adds. "It's a cautionary note," he says. "Those compounds could perhaps cause secondary cancers."

Room to grow

How could cell death favour cancer instead of fighting it? Both teams found that normal PUMA-producing mice activated the kill switch on radiation-damaged cells. But killing off all of those injured cells left a hole that needed to be filled in with fresh material.

Stem cells surged into action, rapidly replicating to fill in the gap. And therein lies the problem, says Villunger. It is likely that those stem cells sustained some damage from the radiation and then were forced to rapidly divide to repopulate the damaged tissue.

The result: a large new population of damaged, potentially cancerous cells.

At present, it's unclear whether the same phenomenon is at work in human cancers. In fact, it is likely that the observation is only relevant in a subset of cancers, notes Gerard Zambetti, a tumour biologist at St Jude Children's Research Hospital in Memphis, Tennessee, who was not involved with the study. Strasser and Villunger studied a particular form of cancer, called thymic lymphoma, caused by repeated exposure to radiation over the course of a month.

"But it's a keystone finding," Zambetti adds. "I imagine there will be a lot of follow-up."

Clinical clues

For now, Villunger and Strasser can point to clinical observations that hint at a role for cell death in spurring cancer. For example, infection with some hepatitis viruses causes repeated damage to the liver and, over time, can lead to cancer. That cycle of damage and regrowth could favour tumour growth, says Villunger.

Similarly, the phenomenon could also explain why patients treated with cancer-fighting chemotherapy are at a higher risk for developing new cancers years down the road, says Strasser.


Strasser's lab has been working with scientists from the biotechnology firm Genentech, located in South San Francisco, California, and the drugmaker Abbott, based in Abbott Park, Illinois, to develop drugs that mimic PUMA. One of these compounds, called ABT-263, has recently completed initial safety studies and is about to move into larger-scale clinical testing, says Strasser.

Although the new work suggests that such drugs, called BH3 mimetics, could foster the growth of new cancers, Strasser says he has more immediate concerns: developing a drug that will activate cell-death pathways without going overboard and killing off healthy tissue. "This is much more important for the current development of the drug than worrying about potential tumours that might arise as a consequence of the treatment 20 years down the track," he says. 

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