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

Stefano Garofalo; Giuseppina D'Alessandro; Giuseppina Chece; Frederic Brau; Laura Maggi; Alessandro Rosa; Alessandra Porzia; Fabrizio Mainiero; Vincenzo Esposito; Clotilde Lauro; Giorgia Benigni; Giovanni Bernardini; Angela Santoni; Cristina Limatola

doi:10.1038/ncomms7623

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

Nat Commun. 2015 Mar 30:6:6623. doi: 10.1038/ncomms7623.

Affiliations

¹ Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
² Université Nice-Sophia Antipolis, IPMC CNRS-UMR, 7275 Valbonne, France.
³ Department of Biology and Biotechnology Charles Darwin, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁴ Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁵ Department of Experimental Medicine, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁶ 1] IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy [2] Department of Neurology and Psychiatry, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁷ 1] Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy [2] IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy.
⁸ 1] Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy [2] IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*
Humans
Interleukin-15 / immunology
Interleukin-15 / pharmacology
Killer Cells, Natural / immunology*
Macrophage Activation
Macrophages / drug effects
Macrophages / immunology*
Mice
Microglia / drug effects
Microglia / immunology*
Neoplasm Invasiveness
Neoplasm Transplantation
Physical Stimulation
Play and Playthings*
Receptor, trkB / drug effects
Receptor, trkB / metabolism
Social Environment
Survival Rate
Tumor Burden / drug effects
rho GTP-Binding Proteins / drug effects
rho GTP-Binding Proteins / metabolism
rhoA GTP-Binding Protein

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
Brain-Derived Neurotrophic Factor
CD68 protein, mouse
Interleukin-15
Receptor, trkB
RhoA protein, mouse
rho GTP-Binding Proteins
rhoA GTP-Binding Protein