Stress has acquired a bad image as a contributor to disease, but a little stress may be no bad thing.
Mice raised in a complex environment providing social interactions, opportunities to learn and increased physical activity are less likely to get cancer, and better at fighting it when they do, a new study suggests. A mild boost in stress hormones seems to be what keeps the cancer at bay by switching on a molecular pathway that restrains tumour growth.
Researchers from the United States and New Zealand injected mice with melanoma cells — the deadliest form of skin cancer. After six weeks, mice raised in an enriched environment — extra-large cages housing 20 individuals with running wheels and other toys — had tumours that were almost 80% smaller than those in mice raised in standard housing — five animals to a cage with no additional stimulation. Whereas all the normally housed mice developed tumours, 17% of the mice from the enriched environment developed no tumours at all. Tests in mice with colon cancer showed the same effect.
“We were very surprised by the degree of the reduction in cancer” in the mice raised under enriched housing conditions, says Matthew During, a neuroscientist at Ohio State University Medical Center in Columbus and a lead author on the study, to be published in Cell tomorrow1.
Researchers studying environmental enrichment have mostly focused on its positive effects on the brain, explains behavioural neuroscientist Abdul Mohammed at the Karolinska Institute in Stockholm, Sweden, who was not involved in the work. “This study is pushing the field to show its effects on tumour growth.”
When During and his colleagues began the work in 2005, he himself had skin cancer, his mother was suffering from ovarian cancer, and a close friend had died of melanoma. “I was interested in the whole question of why the natural history of cancer differed so dramatically from one individual to the next,” he recalls.
The ‘enriched’ mice, the researchers found, had slightly raised levels of stress hormones, but the most striking physiological change was markedly reduced levels of the hormone leptin, known to regulate appetite. Blocking leptin abolished the effects of enrichment, suggesting that the hormone was key to the pathway that led to the anti-cancer effects.
Next, the team looked for changes in the hypothalamus, a brain region that regulates the body’s energy balance and links the nervous system with the endocrine system. They found that expression of a gene encoding the signaling protein BDNF increased dramatically after two weeks in mice living in enriched conditions. And simply overexpressing BDNF in the hypothalamus, the researchers found, mimicked the protective effects of enrichment, suggesting BDNF, too, was a critical regulator of the protective pathway.
Finally, the group found that the increase in BDNF was linked to the decrease in leptin levels in fat cells through the action of stress hormones. “What we’ve really shown here is that the brain, by switching off this pathway, is actually preventing a proliferative environment,” says During.
The health challenge
To make sure that the cancer protection was not simply due to the rodents’ increase in physical activity, the researchers looked for a reduction in cancer among mice housed with the addition of only a running wheel. Running on its own had no effect on tumour growth, and these mice experienced no gain in stress hormone or BDNF expression, nor a dip in leptin levels.
“This is a novel finding,” says John Hall, a physiologist at the University of Mississippi Medical Center in Jackson who studies obesity. “And I think it’s going to stimulate a lot of people to learn more about how enrichment can reduce tumour growth.”
Work by Hall’s group2 and others has begun to hint at leptin’s role in tumour growth. Hall notes, though, that his group’s study suggested that leptin had a relatively weak effect on tumour growth.During stresses that by enriching the rodents’ cage environment “it’s not that you’re just creating a happy place, you’re challenging them”. The protective effects of the stimulation that the test mice received could easily translate into human benefits, he says, and points to possible benefits of a more active lifestyle — not just physically, but also socially and cognitively.
The team is now working to determine which particular elements of the enriched environment are producing its positive effects, During says. They are also developing gene-therapy vectors for delivering BDNF to treat disease, and studying leptin more closely to determine how accurate a marker it is for cancer protection. “Could you then devise interventions, either physiologically or behaviourally,” says During, “and use leptin as a readout?”