All ETDs from UAB

Advisory Committee Chair

Harald Sontheimer

Advisory Committee Members

David Standaert

Michelle Olsen

Peter Smith

Burt Nabors

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant gliomas are the most prevalent primary brain tumor. They are highly aggressive and lack effective treatment options. Standard therapy includes a combination of radiation, chemotherapy, and tumor resection; however, even with aggressive treatment, median patient survival remains a dismal 12 – 14 months after diagnosis. Research has focused on understanding the unique biological mechanisms involved in glioma growth and survival in an effort to design novel therapies to treat this devastating disease. In the unique environment of the brain, gliomas have developed the ability to grow and survive at the cost of the normal surrounding brain tissue. Glutamate, the most abundant excitatory amino acid neurotransmitter, is tightly regulated in the brain to prevent neuronal toxicity and death. Gliomas have developed the ability to disrupt normal glutamate homeostasis to their advantage through alteration of glutamate transporters and receptors. Unlike solid cancers in other organs, tumors growing in the brain are subject to space constraints imposed by a rigid skull. As a result, they must first create space in the brain for continued growth. Through the upregulation of a glutamate transporter, System xc- (SXC), which releases glutamate in exchange for the cystine needed for intracellular synthesis of the antioxidant glutathione (GS), glioma cells release high concentrations of glutamate into the extracellular space. This elevated extracellular glutamate binds neuronal glutamate receptors, causing excitotoxicity and neuronal death. Peritumoral neuronal death provides space for growth and metastasis of glioma cells beyond what would be possible in a fully intact, non-degraded brain. The cystine uptake driving SXC function is important as well, as it increases intracellular concentrations of GSH. GSH functions in cellular redox control, protecting glioma cells from the abundant free radicals created as a result of their increased metabolism. Glioma cells that have less SXC expression have developed the ability to upregulate different glutamate transporters, specifically those in the Excitatory Amino Acid Transporter (EAAT) family. Although these tumors release less glutamate extracellularly, they are able to take up cystine through these glutamate transporters to ensure adequate GSH production and redox control. The importance of these mechanisms to glioma cells is seen in that those tumors that have less ability to take up cystine and release glutamate are slower growing, less malignant, and do not cause tumor-associated seizures as readily as those with abundant SXC expression. Furthermore, γ-aminobutyric acid (GABA), which is synthesized from glutamate, typically an inhibitory neurotransmitter in the brain, exhibits excitatory behavior due to alterations in peritumoral neurons, creating a further propensity toward excitotoxicity and neuronal death. Our findings suggest that targeting SXC-mediated glutamate release may be an important therapeutic strategy for the treatment of malignant gliomas and tumor-associated epilepsy.

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