Disabling cellular assassin prevents cancer

Counterintuitive experiment may help explain why survivors are more vulnerable to other malignancies

Being overly protective can backfire. That’s a lesson that many parents have learned and cancer biologists are beginning to recognize.

Killing off damaged cells is supposed to help protect against cancer, but two new studies show that a massive die-off can lead to the disease instead. The findings, published in the August 1 Genes & Development, may have implications for certain types of cancer therapies, including radiation treatment.

Previous research has demonstrated the importance of p53, a protein that acts as a cell’s security system. The protein senses when a cell is under extreme stress, such as that caused by DNA damage, and dispatches other proteins to deal with the problem in several ways. Some of p53’s minions halt cell growth while others attempt to repair the damage. When all else fails, p53 unleashes Puma, a protein that sets in motion a cell-suicide program called apoptosis.

Apoptosis has long been thought to be one of the most important defenses against cancer, perhaps the most important. So researchers fully expected that mice lacking the Puma protein, and thus the ability to kill damaged cells, would be highly susceptible to cancer after radiation treatment. But in science, even when the result seems like a foregone conclusion, the experiment still has to be done.

So two groups of researchers independently tested the ability of mice genetically engineered to lack the Puma protein to withstand repeated rounds of cancer-inducing radiation exposure.

“It seemed a good way to give a Ph.D. student a solid, but not overly exciting paper,” says Andreas Strasser, a cancer biologist at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, who led one of the groups.

Instead of being riddled with cancer, mice lacking Puma “got no tumors at all” after repeated rounds of radiation exposure, Strasser says.

That left researchers with two possibilities: “Either you’ve snuffed up badly, or something exciting is going on,” he says. Repeating the experiment gave the same result; mice lacking Puma seemed impervious to DNA damage caused by radiation. Another group led by Andreas Villunger, a molecular biologist at Innsbruck Medical University in Austria, found the same result independently.

“The fact that this was found by both groups separately gives added credibility” to the result, says Robert Weinberg, a molecular cancer researcher at MIT’s Whitehead Institute for Biomedical Research in Cambridge, Mass.

But mice with intact Puma — which should have been protected against cancer — developed lymphoma after a couple of rounds of radiation. Both groups of researchers traced the source of the lymphoma to overworked stem cells in the bone marrow.

Under normal conditions, radiation causes so much damage to DNA that blood cells can’t cope and turn on Puma’s cell-suicide program. In that way, about 80 percent of mature blood cells die after a massive dose of radiation.

Surviving stem cells have to “first deal with the DNA damage from radiation, and then they have to expand [their numbers] and regenerate like crazy making new blood cells to save the animal from anemia,” says Villunger. The pressure to reproduce many blood cells quickly puts stress on stem cells and may result in mutations that could lead to cancer the next time stem cells have to work that hard.

Stem cells in mice lacking Puma are spared from the heavy work load, because mature cells survive the radiation onslaught. When Strasser’s group killed off mature blood cells in the mice lacking Puma with drugs called glucocorticoids, the mice got lymphoma, indicating that it’s the initial apoptosis-induced die-off of mature cells and subsequent overworking and overstressing of stem cells that causes the cancer.

The results may help explain why children cured of leukemia often develop other types of cancer 20 or 30 years later, Villunger says. About 15 percent of new cancer cases are new types of tumors arising in cancer survivors, he says. That suggests that the tumors could be related to aggressive treatment of the first cancer, and could mean that doctors should reevaluate how hard they should hit tumors with chemotherapy drugs or radiation.

Of course, “how to deal with this in real life with the patient next to you is complicated,” Villunger says.

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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