Environmental Enrichment Fights CancerG. Scott Lett, Ph.D. CEO, The BioAnalytics Group LLC
Emily G. Patterson-Kane, Ph.D. American Veterinary Medical Association (AVMA) Animal Welfare Division

The article, “Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition,” * was first published in Cell on July 8, and quickly echoed by online editions of major journals including The Scientist, Scientific American, Nature and ScienceDirect. Matthew During, Lei Cao, and their team at The Ohio State University had found that environmental enrichment (EE) diminishes the susceptibility of mice to cancer. Compared to the control mice in a standard cage, the EE mice enjoyed a larger living space, group size, nesting materials and apparatus like wheels, toys and tunnels. When the mice were injected with tumor cells the control animals developed malignant tumors within 15 days. By contrast, the mice living in the EE for 3 weeks prior to cancer inoculation showed significant delay in tumor development and 15 percent of the EE mice had not developed tumors after three weeks. In EE mice that did develop malignancies, the tumors were 43 percent smaller than the tumors of the control mice. Longer exposure to an enriched environment (6 weeks) produced even more dramatic effects.

We have long known that enrichment is beneficial for rodents, promoting neurological development supporting the immune system, but the real implications of these differences have never been made so clear. Not only is reduced susceptibility to cancer a very obvious and significant difference, the study that established this effect was unusually thorough and painstaking. The Ohio team fully investigated this effect over the course of 5 years, studying over 1500 mice. They were able to reproduce similar results in two different cancers (melanoma and colon cancer). They studied variations in the environment to see, for example, whether a single factor (e.g. mouse wheels for greater physical activity) has the same protective effect of the complex EE environment (it doesn’t). They also studied hormonal changes, looking at gene expression data from serum samples, and did over expression and hormonal knock down experiments to isolate potential mechanism of protection. The investigators reported slight upregulation of numerous genes associated with stress, but showed significant upregulation and downregulation of key genes, helping to identify the biochemical mechanisms of protection.

During and Cao’s study is a sobering demonstration that enrichment is not just a humane option for the animals; it is fundamental to scientific validity. It shows that enriched conditions are vital to model the protective mechanisms of normal biological functioning. This research opens exciting avenues for future investigation, but it also raises very challenging questions. If most of our existing disease models are based on animals with compromised base health and vitality, just how does this affect the validity of these models in understanding the progression of disease in normal ‘free range’ humans? And if we need to shift our research baselines by adopting enriched housing, just how disruptive will this be to long-running research projects? How many of our existing painstaking disease models will, or should, survive the transition? If a cancer researcher with 20 years of experience (and accumulated animal data) wants or needs to make a shift to enriched environments for research animals, will it take each of them five years and 1500 mice to change to the new paradigm?

This landmark study suggests that the adoption of enriched housing, as a new standard, will be needed to develop fully valid disease models for conditions that afflict otherwise normal humans. Enrichment advocates need to understand that establishing a new baseline for these studies and adjusting the associated models will be an arduous task, but a necessary one. Part of our task as enrichment advocates must be to acknowledge this obstacle and to encourage people to overcome it. We need to give thought to supporting data and expertise sharing and the development of statistical models and analytical tools for transitioning to enriched baselines, and even funding for the research that will be needed to make the change from standard environment to EE-based studies. And it is unlikely that change will end there, as even enriched housing may not be enough to study the subtle and shifting health challenges of the future. Shifting baselines may be a fact of life for research for some time to come.

Make no mistake, moving to enriched housing will be difficult for researchers with years or decades of data that will be thrown into doubt and confusion by making this change. But it is becoming even clearer that this change is needed, for reasons of animal welfare and scientific validity. For their part, researchers need to fully report housing conditions as an integral part of their research model. And although fully acknowledging housing conditions, as a part of research models will be a difficult step, it will be a significant step closer to truly understanding the terrible diseases biomedical research is trying to conquer.

To learn more:
• Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition Lei Cao1,2 Xianglan Liu1, En-Ju D. Lin1, Chuansong Wang1, Eugene Y.Choi1, Veronique Riban1, Benjamin Lin2, and Matthew J. During1, 2, 3 Cell—9 July 2010 (Vol. 142, Issue 1, pp. 52-64)

Summary
Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural ß-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

• Environmental Enrichment does not Disrupt Standardization of Animal Experiments. Hanno Würbel. ALTEX 24, Special Issue 2007 [Full Text]
• Environmental standardization: cure or cause of poor reproducibility in animal experiments?, Richter, S. H., J. P. Garner, et al. Nat meth—2009 (Volume 6, Issue 4: pp. 257-261.)

1 Departments of Molecular Virology, Immunology and Medical Genetics, and Neuroscience and Neurological Surgery and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
2 Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA
3 Centre for Brain Research, Department of Molecular Medicine & Pathology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland 1023, New Zealand

Issue 5 October 2010

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