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WFlavahan Full Dissertation.pdf (2.91 MB)

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Glioma Stem Cells Adapt to Restricted Nutrition Through Preferential Glucose Uptake

Flavahan, William Alexander
http://rave.ohiolink.edu/etdc/view?acc_num=case1384252748

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Glioblastoma (GBM) remains one of the most lethal human cancers, with conventional treatment offering only palliation. Like all cancers, GBMs display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. This metabolic shift reduces the cells oxygen dependence and provides a steady supply of anabolic material yet requires a steady supply of glucose. In this dissertation, I show that nutrient restriction contributes to tumor progression by enriching for glioblastoma stem cells (GSCs), the most treatment-resistant and regenerative of GBM cells. This enrichment is due to both preferential GSC survival and adaptation of non-GSCs through acquisition of stem-like features. GSCs outcompete for glucose uptake by co-opting the high-affinity neuronal glucose transporter isoform, type 3 (GLUT3). In the normal brain, glucose is an essential fuel for neuronal metabolism; yet vascular glucose delivery is physiologically stymied by the blood brain barrier. In response to this, neurons express GLUT3, allowing steady glucose uptake from a glucose-poor microenvironment. GSCs preferentially express GLUT3 and targeting GLUT3 inhibits GSC growth and tumorigenic potential, suggesting GLUT3 is a marker of CSCs. GLUT3, but not GLUT1, correlates with poor survival in brain tumors and other solid cancers in clinical patient datasets; thus, CSCs in many cancer types may extract nutrients with high affinity. Given the restricted expression profile of GLUT3 in non-malignant tissue and the critical role of GLUT3 in CSC biology, therapeutic targeting of GLUT3 may prove to be a viable treatment across multiple cancer types.
Jeremy Rich, MD (Advisor)
Xiongwei Zhu, PhD (Committee Chair)
Jan Jensen, PhD (Committee Member)
Robert Silverman, PhD (Committee Member)
Robert Weil, MD (Committee Member)
Anita Hjelmeland, PhD (Committee Chair)
119 p.
Biology; Biomedical Research; Cellular Biology; Molecular Biology; Neurobiology
cancer; glioblastoma; glioma; cancer stem cells; glioblastoma stem cells; glucose; glucose uptake; GLUT3

Recommended Citations

Citations

  • Flavahan, W. A. (2014). Glioma Stem Cells Adapt to Restricted Nutrition Through Preferential Glucose Uptake [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1384252748

    APA Style (7th edition)

  • Flavahan, William. Glioma Stem Cells Adapt to Restricted Nutrition Through Preferential Glucose Uptake. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1384252748.

    MLA Style (8th edition)

  • Flavahan, William. "Glioma Stem Cells Adapt to Restricted Nutrition Through Preferential Glucose Uptake." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1384252748

    Chicago Manual of Style (17th edition)

case1384252748
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© 2013, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.