title: Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity.
abstract: Glioblastomas continue to rank among the most lethal primary human tumors. Despite treatment with the most rigorous surgical interventions along with the most optimal chemotherapeutic and radiation regimens, the median survival is just 12-15 mo for patients with glioblastoma. Among the histological hallmarks of glioblastoma, necrosis has been demonstrated to be a powerful predictor of poor patient prognosis. Over the years, there have been many advances in our understanding of the molecular mechanisms underlying glioblastoma formation, yet the mechanisms that lead to tumor necrosis remain unclear. One pathway that may lead to necrosis in glioblastoma involves the neurotransmitter, glutamate, which has been shown to accumulate in the peritumoral fluid as a result of decreased cellular uptake by glioblastoma cells. This accumulation leads to subsequent glutamate excitotoxicity and probable necrosis through a massive elevation of intracellular Ca(2+) and reduction in cellular ATP levels. We propose that a pathway involving tumor necrosis factor-alpha (TNFalpha), astrocyte-elevated gene-1 (AEG-1) and nuclear factor-kappaB (NFkappaB) leads to decreased glutamate uptake through coordinated downregulation of the excitatory amino acid transporter 2 (EAAT2), the glutamate transporter responsible for the majority of glutamate uptake in the human brain. In addition, we suggest that AEG-1 signaling, loss of phosphatase and tensin homolog (PTEN), and ionotropic glutamate receptor activity lead to AKT pathway activation, which results in nutrient overconsumption and necrosis. Together, these pathways provide a new perspective on glioblastoma necrosis involving the process of glutamate excitotoxicity. Future research should address the components of these molecular pathways in order to better understand the mechanism of necrosis in glioblastoma and to begin to develop targeted therapies that may improve patient prognosis in the future.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Noch
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D009336:Necrosis
chemical_list: D005971:Glutamates