Glutamate synapses bioelectrically into glioma cells to drive tumor progression

The relationship between human neurostructural structure and glioma has been deeply studied.
and side secretion effects of classical neurotransmitters are associated with the progression of gliomas and other brain tumors.
, glutamate, in particular, binds to different types of glutamate limes to improve the proliferation, survival and invasion of brain tumor cells.
addition, tumor microtubes (tumour microtubes, TM) promote the progression and resistance of incurable gliomas, especially glioblastomas (GBM) and low-level astrocytes.
TM is essential for the invasion and proliferation of glioma cells, connecting individual tumor cells to functional communication networks.
The Institute of Anatomy and Cell Biology at the University of Heidelberg in Germany, the National Cancer Center and Varun Venkataramani of the German Cancer Research Center studied the direct communication channels between neurons and glioma cells: real functional chemical synapses between synhapus pre-neurons and post-synhapus glioma cells, published in the September 2019 issue of Nature.
the results, the researchers first observed typical characteristics of chemical synapses when examining TM using an electron microscope.
Then explore the structure of neurogliotic synapses (NGS) in different brain tumor models, including heterogeneum transplant models of human-source glioma cell line, co-culture models with neurons, and adult glioma surgical specimens;
NGS contains pre-synapse vesicles, synactical clearances with dense electrons, pre-synctic active zone substitums for butt vesicles, and post-synhapous dense material regions, with all the signature features of glutamate-energy chemical synapses.
NGS is made up of pre-synapse neurons and post-synapse glial cells, and TM can be observed on NGS in most glioma cells.
in models of less protrusive glioblastoma and meningoma, no synapses between neurons and brain tumor cells were detected, and these two brain tumors were curable and did not form TM during growth.
In incurable human gliomas and mouse models, the formation of NGS was consistent, but NGS did not form in less malignant primary brain tumors, indicating that NGS had a particular effect on the malignant characteristics of asaid gliomas, including glioblastomas.
researchers studied the molecular composition of NGS using ultra-distinguished 3D direct random optical reconstruction microscopes (direct stochastic optical reconstruction microscopy, dSTORM), concentromoscopes, single-cell gene expression data for human glioma, 3D electron microscopes, and immunofluorescent staining.
found that glutamate-energy methylphosphate (AMPAR) in NGS is a strict point pattern tissue that overlaps with glutamate-enabled pre-synapse vesicle clusters; glutamate-powered NGS is often expressed on interconnected TM networks; and strong TM-connected glioma cell subsysty, a known incurable glioma driver, showing molecular characteristics that contain functional AMPAR synhapus contact.
researchers further analyzed the functional characteristics of NGS in different models, including tissue surgically removed from glioblastoma, GBM cells that steadily express GFP or tdTomato, fresh brain tissue smears in foreign transplant mice, and GBM cells cultured with neurons.
found spontaneous excitatory postsynaptic currents (sEPSCs) in GBM cells, suggesting the presence of functional NGS in human diseases.
, in all human glioma samples and disease models, sEPSCs had the same amplitude, rise time, and attenuation dynamics, consistent with established glutamate-energy synapses.
In addition, the researchers found that spontaneous slow intronate currents (slow inward currents, SICs) were present in fresh brain tissue smears of GBM cells and neuron co-culture and heterogeneity transplant models;
known calcium ion signal is the communication center within the glioma.
, the researchers looked at the coupling of SIC and EPSC in GBM cells with in-cell calcium signals.
found that GBM cells were not excited by bioelectricals, and that a series of induced EPSCs produced calcium glioma signals; After the photogenetic stimulation of neurons, GBM cells showed that the transient frequency of calcium ion signal increased and showed a synchronized pattern of calcium activity, which greatly exceeded the frequency of transient and spontaneous glioma network activity of spontaneous calcium ion signal, and the number of GBM cells acting together after ChR2 stimulation increased significantly.
further analysis showed that synactus-stimulated subpopulations of GBM cells were able to transmit calcium ion signals to the remaining TM-connected glioma networks.
, the results confirm that calcium ions can enter GBG cells through AMPAR and other electrolyte ions, and that neuron activity can lock the time of the GBM cell network and cause clinical calcium ion signals.
researchers are trying to shed light on the biological consequences of NGS input on GBM cell invasion and proliferation, which are two keys to the tumor's progression.
by detecting calcium ion signals activated by neurons, it was found that the subpops of GBM cells connected to neuron function in the body were more invasive than other GBM cells.
the migration of tumor cells is related to the frequency of calcium ion signals and is causal.
, when the AMPAR signal is genetically disturbed, the invasion of GBM cells in the body decreases, indicating that NGS-driven calcium-dependent GBM cell activation directly affects the invasiveness of GBM cells.
In studying whether tumor cell proliferation and eventual glioma progression are affected by NGS, researchers found that genetically and pharmacologically blocking AMPAR signaling path paths and blocking synth communication between NGS-driven neurons and GBM cells can reduce the malignancy of GBM cells, thus slowing the progression of gliomas.
non-competitive AMPAR antagonist perampanel is a class of anti-epileptic drugs that have potential anti-tumor effects in glioma patients.
long-term treatment of heterogenetic transplant mice can reduce the proliferation of GBM cells.
conclusion, the results show that in the network of brain tumor cells connected by TM, glutamate can stimulate the invasion and growth of glioma by affecting calcium ion signals.
these complex glioma loop dynamics mechanisms make synhapus transfer regulators, such as amPAR inhibitory anti-epileptic drug perampanel, an interesting candidate in preclinical research and clinical trials.
addition, most clinically incurable glioma patients have seizures, and repeated seizures or exacerbations are associated with the recurrence of malignant gliomas.
suggests a contrary causal relationship: excessive neuron activity during seizures actually stimulates the progression of brain tumours.
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