Environmental enrichment triggers mouse wound repair response

April 25, 2017

Living in a stimulating environment has a wide range of health benefits in humans and has even been shown to fight cancer in mice, but the underlying mechanisms have been unclear. A study published April 25 in Cell Reports reveals that cognitive stimulation, social interactions, and physical activity increase lifespan in mice with colon cancer by triggering the body's wound repair response.

"The bottom line is that there are many benefits with minimal risks to reducing stress through mind-body interventions," says senior author Melinda Angus-Hill of the Huntsman Cancer Institute at the University of Utah. "However, more research is essential to define whether mind-body interventions drive a wound repair response in colon tumorigenesis in humans."

Mind-body medicine focuses on reducing the physiological manifestations of stress and anxiety by improving social and cognitive stimulation, as well as physical activity. A growing body of evidence suggests that mind-body medicine can significantly improve overall health. For example, epidemiological studies have found that depression, stress, and social isolation increase the risk of cancer progression. However, the molecular and cellular mechanisms underlying these effects have not been clear.

To address this question, Angus-Hill and her team exposed mice with colon cancer to environmental enrichment by housing them in cages filled with many other mice, along with running wheels, tunnels, huts, igloos, and nesting materials. The researchers found that exposure to stimulating surroundings increased the lifespan of male and female mice with colon tumors (55 days and 82 days, respectively) but most likely through different mechanisms. Environmental enrichment reduced tumor size in females but decreased blood levels of inflammatory molecules in males.

A reduction in inflammation is a key step in the wound repair process, and it has long been recognized that tumors resemble wounds that do not heal. So the researchers suspected that environmental enrichment might also trigger other steps of the wound repair process, thereby improving the survival of male mice with colon cancer. Consistent with this idea, they found that environmental enrichment activated nuclear hormone receptor signaling pathways involved in wound repair and improved tumor vasculature in male mice with colon cancer.

Blood vessels in the tumor microenvironment are often nonfunctional, preventing cancer drugs from reaching their target. Therefore, these findings suggest that environmental enrichment could improve the delivery of chemotherapeutic or immunotherapeutic agents to the colon tumor. "Our findings support additional studies into the future application of mind-body intervention in combination with conventional therapy for patients with colorectal cancer," Angus-Hill said.

Moreover, environmental enrichment stimulated immune cells called plasma cells to produce an antibody called Immunoglobulin A (IgA), which attached to the surface of pericytes located on the outside of blood vessels. The activated, IgA-bound pericytes then migrated to and replaced glandular structures at the periphery of tumors, thereby sealing the wound in a process similar to scarring. Ultimately, the wound repair process restored the integrity of the colon barrier, defended against pathogens, and improved the composition of gut microbes, thereby reducing inflammation.

"Our study demonstrates a positive role of environmental enrichment-induced IgA secreting plasma cells and raises the possibility of harnessing their potential for therapeutic purposes in colon cancer, particularly in people who practice stress reduction techniques and who are physically active," Angus-Hill says.

Based on these findings, Angus-Hill and her team are now planning on initiating clinical trials to study the effects of mind-body therapy in patients with colon cancer. They would also like to examine how environmental enrichment improves the survival of female mice with colon cancer and what explains the different effects between the sexes. Another important goal will be to pinpoint the molecular mechanisms that are essential for the beneficial effects of wound repair following environmental enrichment. "This could aid in developing pharmacological strategies that mimic mind-body medicine," Angus-Hill says. "The availability of a pharmacological treatment to effortlessly reduce stress would be invaluable for cancer and disease prevention and treatment."
The project was supported by the National Cancer Institute and the Huntsman Cancer Foundation.

Cell Reports, Bice et al.: "Environmental Enrichment Induces Pericyte and IgA-Dependent Wound Repair and Lifespan Extension in a Colon Tumor Model" http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30481-3

Cell Reports (@CellReports), published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit: http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact press@cell.com.

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