Pathway analysis of glutamate-mediated, calcium-related signaling in glioma progression

Brain tumors, particularly high-grade glioblastomas, are a crucial public health issue due to poor prognosis and an extremely low survival rate. The glioblastoma multiforme (GBM) grows rapidly within its unique microenvironment that is characterized by active neural communications. Therefore, diverse neurotransmitters not only maintain normal brain functions but also influence glioma progression. To fully appreciate the relationship between neurotransmitters and glioma progression, we reviewed potential neurotransmitter contributors in human GBM and the much less aggressive Low-grade glioma (LGG) by combining previously published data from gene-mutation/mRNA sequencing databases together with protein-protein interaction (PPI) network analysis results. The summarized results indicate that glutamatergic and calcium signaling may provide positive feedback to promote glioma formation through 1) metabolic reprogramming and genetic switching to accelerate glioma duplication and progression; 2) upregulation of cytoskeleton proteins and elevation of intracellular Ca²⁺ levels to increase glutamate release and facilitate formation of synaptic-like connections with surrounding cells in their microenvironment. The upregulated glutamatergic neuronal activities in turn stimulate glioma growth and signaling. Importantly, the enhanced electrical and molecular signals from both neurons and glia propagate out to enable glioma symptoms such as epilepsy and migraine. The elevated intracellular Ca²⁺ also activates nitric oxide synthase to produce nitric oxide (NO) that can either promote or inhibit tumorigenesis. By analyzing the network effects for complex interaction among neurotransmitters such as glutamate, Ca²⁺ and NO in brain tumor progression, especially GBM, we identified the glutamatergic signaling as the potential therapeutic targets and suggest manipulation of glutamatergic signaling may be an effective treatment strategy for this aggressive brain cancer.