Environmental Enrichment Induces Pericyte and IgA-Dependent Wound Repair and Lifespan Extension in a Colon Tumor Model

• Published in: Cell reports (Cambridge) Vol. 19; no. 4; pp. 760 - 773
• Main Authors: Bice, Benjamin D., Stephens, Megan R., Georges, Stephanie J., Venancio, Ashlee R., Bermant, Peter C., Warncke, Annika V., Affolter, Kajsa E., Hidalgo, Julio R., Angus-Hill, Melinda L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2017; Elsevier
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Alphaproteobacteria - isolation & purification; Alphaproteobacteria - physiology; Animals; Colon - microbiology; colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - mortality; Colonic Neoplasms - pathology; Cytokines - blood; Disease Models, Animal; Environment; environmental enrichment; Female; IgA; Immunoglobulin A - metabolism; Male; Mice; Microbiota; mind-body medicine; Neovascularization, Physiologic; nuclear hormone receptors; pericytes; Pericytes - cytology; Pericytes - metabolism; Proteobacteria - isolation & purification; Proteobacteria - physiology; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Survival Rate; Transcription Factor 4 - genetics; Transcription Factor 4 - metabolism; Wound Healing - physiology; wound repair; environmental enrichment; microbiota; IgA; wound repair; colon cancer; pericytes; nuclear hormone receptors; mind-body medicine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.04.006

Environmental enrichment (EE) replicates mind-body therapy by providing complex housing to laboratory animals to improve their activity levels, behavior, and social interactions. Using a Tcf4Het/+ApcMin/+-mediated model of colon tumorigenesis, we found that EE vastly improved the survival of tumor-bearing animals, with differential effect on tumor load in male compared to female animals. Analysis of Tcf4Het/+ApcMin/+ males showed drastically reduced expression of circulating inflammatory cytokines and induced nuclear hormone receptor (NHR) signaling, both of which are common in the wound repair process. Interestingly, EE provoked tumor wound repair resolution through revascularization, plasma cell recruitment and IgA secretion, replacement of glandular tumor structures with pericytes in a process reminiscent of scarring, and normalization of microbiota. These EE-dependent changes likely underlie the profound improvement in survival of colon-tumor-bearing Tcf4Het/+ApcMin/+ males. Our studies highlight the exciting promise of EE in the design of future therapeutic strategies for colon cancer patients. [Display omitted] •Environmental enrichment (EE) enhances the lifespan of colon-tumor-bearing mice•EE activates nuclear hormone receptor signaling commonly involved in wound repair•EE resolves the wound repair process in tumors through IgA and pericyte activities•EE normalizes gut microbiota and improves microbe biodiversity Tumors are characterized as wounds that do not heal. Bice et al. show the beneficial effects of environmental enrichment on tumorigenesis in a mouse model of colon cancer. The authors demonstrate that EE improves the lifespan of tumor-bearing animals through the restoration of a wound-repair-like response within the tumor.