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

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

doi:10.1038/ncomms7623

Stefano Garofalo, Frederic Brau + Show 12 more

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https://doi.org/10.1038/ncomms7623

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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.

Highlights

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 describe that IL-15 increases NK1.1 þ and CD69 þ cell infiltration in tumour area and that natural killer (NK) cell depletion reduces the efficacy of IL-15 administration on tumour growth and of EE on tumour growth and mice survival
As control of EE efficacy, the effect on hippocampal synaptic plasticity was tested[9]: mice housed in EE have a robust increase in long-term potentiation (LTP) expression, versus standard environment (SE) mice, as measured by field excitatory postsynaptic potential recordings in the CA1 region (Supplementary Fig. 1b; LTP evoked by 100 Hz train)

Summary

Introduction

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/Mf) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. We choose malignant glioma as it is the most diffuse and aggressive neoplasm of the nervous system, characterized by high invasiveness and proliferation, diffuse apoptosis and/or necrosis, astrogliosis and microglia/macrophage (M/Mf) activation, with a poor prognosis To this aim, we transplanted murine glioma (GL261) into the brain of mice housed in EE or in SE. BDNF has direct effects on tumour cells, reducing glioma cell migration in vitro and impairing the expression of the phagocytic marker CD68 on M/Mf, and their infiltration in the tumour mass These novel results encourage clinical trials testing the effect of EE, IL-15 and BDNF in humans suffering from malignant glioma

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