Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice

• Published in: Nature communications Vol. 6; no. 1; p. 6623
• Main Authors: Garofalo, Stefano, D’Alessandro, Giuseppina, Chece, Giuseppina, Brau, Frederic, Maggi, Laura, Rosa, Alessandro, Porzia, Alessandra, Mainiero, Fabrizio, Esposito, Vincenzo, Lauro, Clotilde, Benigni, Giorgia, Bernardini, Giovanni, Santoni, Angela, Limatola, Cristina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.03.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 14; 59; 631/250/2504; 631/378/340; 631/67/1922; 64; 64/60; 82; 82/51; 9/30; 96; 96/21; 96/31; 96/63; Animals; Antigens, CD - drug effects; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - drug effects; Antigens, Differentiation, Myelomonocytic - metabolism; Brain-Derived Neurotrophic Factor - immunology; Brain-Derived Neurotrophic Factor - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Environment; Glioma - immunology; Glioma - mortality; Glioma - pathology; Humanities and Social Sciences; Humans; Infiltration; Interleukin-15 - immunology; Interleukin-15 - pharmacology; Killer Cells, Natural - immunology; Macrophage Activation; Macrophages - drug effects; Macrophages - immunology; Mice; Microglia - drug effects; Microglia - immunology; multidisciplinary; Neoplasm Invasiveness; Neoplasm Transplantation; Physical Stimulation; Play and Playthings; Receptor, trkB - drug effects; Receptor, trkB - metabolism; rho GTP-Binding Proteins - drug effects; rho GTP-Binding Proteins - metabolism; Science; Science (multidisciplinary); Social Environment; Survival Rate; Tumor Burden - drug effects; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7623

Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment. Enriched environment is known to be beneficial in several disease settings. Here the authors show that mice pre-exposed to enriched environment survive longer when challenged with glioma due to increased antitumour immunity, and identify soluble factors that mediate these effects.