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Better housing fights cancer in mice

Enriching animals' environments does much more than improve their psyches -- it may fight deadly disease, according to a study published online today (July 8) in Cell.

Living in larger spaces with access to more toys and companions helped shrink, or even eliminate, tumors in cancerous mice.


"The findings are very interesting and also very provocative," said physiologist John Hall of the University of Mississippi Medical Center, who was not involved in the research. "[An] enriched environment can reduce tumor growth, I think that's clear."


The results may have important implications for cancer research, added neuroscientist Anthony Hannan of the Howard Florey Institute in Melbourne, Australia, who also did not participate in the study, in an email to The Scientist. For example, "an experimental drug might show different effects in a preclinical trial, depending on whether the animals are housed with enrichment objects, or in a more sparse environment."


Providing rodents with an enriched environment leads to a number of neurological changes in the brain, and can impact the progression of neurological diseases. But how the enriched environment influences cancer growth is not clear.


To answer this question, neuroscientist Matthew During of The Ohio State University College of Medicine and his colleagues gave some mice a housing upgrade -- from standard mouse cages with 4 other mice to living areas 40 times larger, with more hiding places, more playmates (15 to 20 animals), and more toys. The team then injected enriched and normal mice with melanoma cells and monitored the progression of tumor growth.


Remarkably, just two and half weeks later, mice housed in the enriched environments for 3 weeks prior to inoculation had tumors that were 43 percent smaller (by volume) than those housed in normal cages. Tumors of mice in enriched environments for 6 weeks before the injection were 77 percent smaller (by weight) than those in control mice. Furthermore, some of the mice in enriched environments had no visible tumors at all, whereas all of the control mice had solid masses.


"The result was very robust and much more profound and much more exciting than we had predicted," During said. It was so shocking, the researchers repeated the experiment over the course of 5 years with some 1,500 mice to verify the results. They even demonstrated the protective effect of the enrichment in another cancer model -- colon cancer.


Their results show that "sensory, cognitive and motor stimulation can protect against many diseases, and not just those involving the brain," said Hannan.


Now, During said, "the question is really to find out the aspects of the environment" that are causing the tumors to shrink. The effects cannot be attributed purely to increased exercise, for example, as non-enriched mice that ran on wheels for 4 weeks prior to inoculation did not see a reduction in tumor growth.


Delving into the mechanism by which the environment might be inducing its protective effects, the researchers identified several key players, including brain-derived neurotrophic factor (BDNF), the expression of which is known to be influenced by activity and environment. Overexpression of BDNF mimicked the results of the enriched environment, and knocking down BDNF blocked the effects of the enriched environment on tumor growth.


Furthermore, the scientists saw a steep reduction in leptin -- a protein hormone that plays a role in regulating appetite and metabolism -- in mice in enriched environments. Knowing that leptin expression is regulated at least in part by the sympathetic nervous system, they tested the effects of a ?-blocker known as propranolol, which inhibits that system, and found that it the drug completely blocked the effects of the enriched environment on tumor growth.


The role of BDNF in this process makes sense, researchers agree, but other aspects of this proposed mechanism "are somewhat provocative and might be challenged in the future," Hall said. For example, ?-blockers have long been used for the treatment of high blood pressure, he said. "If they actually had an effect to promote tumor growth, I think that would have been seen in humans."


In addition to potential implications of this work for developing a cancer therapeutic -- which During and his team are now looking into -- there are more basic considerations about how to house laboratory animals, Hannan said. "The dramatic effects shown in this Cell paper, together with many previous papers on rodent models of brain disorders, suggest that all biomedical researchers (not just neuroscientists) need to think carefully about housing conditions and other environmental factors in their experiments."


Citation: L. Cao, et al., "Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition," Cell 142: 52-64, 2010.