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Challenging Cancer: A Stressful Lifestyle Reduces Tumor Growth in Mice

Mice raised in a challenging environment had more robust immune responses and hormonal changes, factors that may help protect against cancer



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Stress is often linked to heart disease and other ailments, but a new study suggests that the strains of living in crowded and challenging physical environments might mitigate against cancer. Scientists found that simply placing mice afflicted with cancer in a more complex living environment resulted in a remarkable reduction in tumor growth.

While eating a healthy diet and reducing exposure to carcinogens are certainly important ways to reduce cancer risk, the results show that other components of the environment like an individual's surroundings, social interaction and mental state may also have profound impacts on cancer.

To examine how living conditions might affect cancer development, Matthew During of The Ohio State University Comprehensive Cancer Center and colleagues raised mice in either standard laboratory housing (five mice per cage) or in an enriched environment with more room, a greater number of mice (18 to 20 animals), and more challenges and activities (running wheels, tunnels, toys, mazes and nesting material). Mice were then injected with tumor cells, which led to malignancies in all of the control animals within 15 days. By contrast, the rate of tumor formation in animals living in the enriched environment was significantly delayed, and 15 percent had not developed tumors after nearly three weeks; when tumors were visible, they were 43 percent smaller than the lesions on control animals.

"Up front, we didn't really know whether this would be good or bad for cancer," says During, professor of molecular virology, immunology and medical genetics. "We were amazed that the effect was very pronounced," he adds. The study was published online July 8 in Cell .

The cancer resistance was not simply due to increased physical activity, however, because animals that only exercised more did not experience the same benefits. During says he suspects that the key may lie in the more diverse social encounters experienced by the mice in the enhanced environment.

"These [enriched] environments are somewhat stressful for the animals. They're not in a happy place," During says. "It's a more wild, challenging environment."

Consistent with this, the animals in the augmented setting had a slightly elevated stress hormone level as well as stronger immune systems. During noted that the most consistent and dramatic finding, however, was a nearly 90 percent drop in leptin, a hormone produced by fat that helps regulate metabolism. In humans elevated leptin levels are associated with a greater risk of some cancers, including melanoma, breast and prostate malignancies.

The scientists then traced the leptin decline to a pathway that originates in the brain's hypothalamus. They discovered that animals living in the enriched environment had higher levels of a protein called brain-derived neurotrophic factor (BDNF). To determine the role of BDNF in tumor resistance, the scientists engineered an increase in BDNF in the control mice and found that the leptin levels in the animals decreased, their immune systems were boosted, and their tumors shrank. Conversely, eliminating BDNF in the more stimulated mice blocked their lifestyle's tumor-protective effects. These experiments confirmed that the environment-induced increase of BDNF in the brain and consequent decline in leptin were causatively involved in the observed beneficial effects.

"The dramatic effects of environmental enrichment on mouse models of cancer were surprising," says Anthony Hannan, head of the Neural Plasticity Laboratory at the University of Melbourne who was not involved in the study. Hannan, who studies how environmental enrichment benefits certain brain disorders, says this set of findings will have a great impact on the field. He has previously proposed the use of drugs that mimic or enhance the beneficial effects of environmental stimulation for the treatment of brain disorders; this study, he says, suggests that such "enviromimetic" drugs might be also be developed to treat cancer or other non-neurological diseases.

In addition to developing molecular therapeutics, During would like to narrow the environmental factors involved to try to better define those lifestyle changes that may be important for cancer prevention.

Whereas most people live in fairly safe environments, with plenty of food and some degree of social interaction, "our data suggests that we shouldn't just be avoiding stress, we should be living more socially and physically challenging lives," During says.

"Optimizing levels of complex mental stimulation and physical activity in our population could have major public health implications for a wide range of devastating diseases," Hannan says. "However, large controlled clinical trials and epidemiological studies need to be performed to provide evidence following up the animal studies," he adds.

 

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