Bidirectional Neuron-glioma interactions: effects of Glioma Cells on Synaptic activity and its impact on tumor growth

Gliomas grow in a neuronal environment, but the interactions between glioma cells and peritumoral neurons remain poorly understood. Understanding this complex relationship could add useful information to develop more effective therapeutic approaches for the treatment of this deadly disease. In recent years, the interaction between cancer cells and tumor microenvironment has emerged as one important regulator of tumor progression. Thus, my thesis aimed to investigate the crosstalk between neural peritumoral tissue and glioma cells; in particular, I assessed i) functional impairments of peritumoral tissue occurring during tumor progression and ii) the impact of neural activity on glioma proliferation. To monitor longitudinal changes in network activity, I recorded visual evoked potentials (VEP) and local field potentials (LFP) after transplant of GL261 glioma cells (or PBS) in mouse visual cortex. Gliomas were injected in visual cortex to allow a detailed investigation of peritumoral neurons using several physiological parameters. Thanks to this analysis, I detected a progressive deterioration of VEP amplitudes along with tumor progression and changes in the LFP power spectra typical of focal epilepsy, with an increase of the power of delta band and the deterioration of alpha rhythm in glioma-bearing mice. To understand the molecular alterations that underlie these perturbed patterns of neuronal activity, I analysed the gene expression profile of microdissected peritumoral pyramidal neurons in the cortical superficial layers (i.e., II-III). The data were clear in indicating that glioma induces alterations in both pre- and post-synaptic markers, demonstrating that its progression shapes the network activity of peritumoral areas towards hyperexcitability. Indeed, I recorded the occurrence of seizures in a subset of glioma-bearing animals, finding alterations in the LFP power spectra just before the onset of ictal events. To investigate how levels of cortical activity affects tumor cell proliferation, I inoculated GL261 glioma cells into the mouse neocortex and modulated neuronal activity by different methods. Second, I dissected the role of inhibitory and excitatory circuitries on tumor proliferation and I found that while the activation of excitatory networks exacerbate glioma proliferation (confirming the data in literature), inhibitory circuits decrease GL261 cell proliferation. Based on these data, I investigated whether a sensory stimulation of the visual cortex may also impact on tumor growth. I found that a reduction of visual cortical activity via Dark Rearing enhanced the density of proliferating glioma cells, while a Visual Stimulation had the opposite effect. Intriguingly the effect was region-specific, as visual deprivation had no significant effect on glioma proliferation in motor cortex. I found that local blockade of neurotransmission via administration of the synaptic blocker botulinum neurotoxin A (BoNT/A) enhances glioma cell proliferation, underlying the importance of neural activity in controlling glioma progression. In addition, the stimulation with visual patterns combined with temozolomide treatment delayed the deterioration of visual responses induced by glioma growth. Altogether, these data demonstrate complex effects of different neuronal subtypes and afferent sensory input in the control of glioma proliferation.