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The Role of Hypoxia in Modulating Glioma Cell Tumorigenic Potential

Heddleston, John Michael
http://rave.ohiolink.edu/etdc/view?acc_num=case1310043767

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Cell Biology.
Normal stem cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic stem cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and typically contains regions of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. The cellular heterogeneity of GBM is organized into a hierarchical structure; at the apex of the hierarchy is a self-renewing, tumorigenic, glioma stem cell (GSC). The significance of GSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Recent experimental evidence has supported the importance of hypoxia in GSC niches. I hypothesized that hypoxia promotes a GSC-like phenotype within GBM and does so through HIF2α. Furthermore, HIF2α requires epigenetic modifying proteins for downstream signaling and promoting tumor malignancy in GBM. Here I demonstrate that culture in restricted oxygen or overexpression of HIF2α increases GSC-related gene expression and promotes tumor propagation in nonstem glioma cells. The hypoxic response in GBM is regulated by the lysine histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1). MLL1 is induced by hypoxia and required for upregulation and downstream function of HIF2α, but not HIF1α. Targeting MLL1 by RNA interference inhibited expression of HIF2α and target genes, including VEGF. GSCs expressed higher levels of MLL1 than matched nonstem tumor cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism linking GBM epigenetic modifying proteins to tumor propagation via the hypoxic niche. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different epigenetic mechanisms. My work provides a rationale for more sophisticated therapeutic approaches and indicates that disrupting the GSC hypoxic niche and targeting GSC epigenetics may improve patient outcome in the struggle against GBM.
Jeremy Rich, MD (Advisor)
Danny Manor, PhD (Committee Chair)
George Stark, PhD (Committee Member)
Erik Andrulis, PhD (Committee Member)
219 p.
Cellular Biology; Molecular Biology
glioma stem cell; hypoxia; HIF; epigenetic; MLL1; tumorigenicity

Recommended Citations

Citations

  • Heddleston, J. M. (2011). The Role of Hypoxia in Modulating Glioma Cell Tumorigenic Potential [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1310043767

    APA Style (7th edition)

  • Heddleston, John. The Role of Hypoxia in Modulating Glioma Cell Tumorigenic Potential. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1310043767.

    MLA Style (8th edition)

  • Heddleston, John. "The Role of Hypoxia in Modulating Glioma Cell Tumorigenic Potential." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1310043767

    Chicago Manual of Style (17th edition)

case1310043767
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© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.