All ETDs from UAB

Advisory Committee Chair

Harald Sontheimer

Advisory Committee Members

Burt Nabors

Michelle Olsen

Peter Smith

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

Glioblastoma multiforme (GBM) are the most prevalent and aggressive malignant brain tumors. Current treatment - a combination of radiation, chemotherapy and resection - has limited effectiveness and offers poor prognosis. In this study, we examined the roles of system xc- (SXC) and excitatory amino acid transporters (EAATs), which transport the amino acids cystine and glutamate, on tumor growth, neurotoxicity, and peritumoral seizure activity. Tissue micro-arrays from 45 patients were examined by immuno-histochemistry, comparing tumor-bearing tissue and adjacent normal brain. Using a novel flank tumor propagation technique, we chose 3 glioma samples with varying SXC and EAAT expression levels to study their physiological differences using cell and tissue assays. Examination of patient tissues indicated glioma patients can be stratified into high or low level system xc- expressers, compared to normal brain. In low SXC expressing tumors, cystine uptake assays suggested an alternative transporter supplying intracellular cystine for GSH synthesis and redox protection; EAAT1 and EAAT3 were discovered to mediate this alternative transport. High SXC expression correlated with increased proliferation over 5 days, neurotoxicity in 48 and 72 hour glioma/neuron co-cultures, and a significant 67.8% increase in seizure prevalence upon intracranial implantation in vivo. Furthermore, system xc- inhibition using Sulfasalazine, an FDA approved drug, resulted in decreased proliferation of all tumor lines expressing SXC, and decreased cystine uptake and neurotoxicity in tumor lines expressing high levels of SXC and no EAATs, during the same time points. Our results suggest that SXC should be further investigated as a prognostic marker for tumor growth and seizure activity as well as a therapeutic marker for glioblastoma patients, as our data argues for adjuvant Sulfasalazine administration in patients with glioblastomas expressing SXC.

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