Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens

Authors

  • John J. P. Kelly,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Cell Biology and Anatomy, Calgary, Alberta, Canada
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  • Owen Stechishin,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Cell Biology and Anatomy, Calgary, Alberta, Canada
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  • Andrew Chojnacki,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Cell Biology and Anatomy, Calgary, Alberta, Canada
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  • Xueqing Lun,

    1. Clark Smith Integrative Brain Tumor Research Center and Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada
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  • Beichen Sun,

    1. Clark Smith Integrative Brain Tumor Research Center and Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada
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  • Donna L. Senger,

    1. Clark Smith Integrative Brain Tumor Research Center and Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada
    2. Department of Oncology, Calgary, Alberta, Canada
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  • Peter Forsyth,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Clark Smith Integrative Brain Tumor Research Center and Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada
    3. Department of Oncology, Calgary, Alberta, Canada
    4. Department of Clinical, Neurosciences, Calgary, Alberta, Canada
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  • Roland N. Auer,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Clinical, Neurosciences, Calgary, Alberta, Canada
    3. Department of Pathology and Laboratory Medicine, Calgary, Alberta, Canada
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  • Jeff F. Dunn,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Diagnostic Imaging, University of Calgary, Calgary, Alberta, Canada
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  • J. Gregory Cairncross,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Oncology, Calgary, Alberta, Canada
    3. Department of Clinical, Neurosciences, Calgary, Alberta, Canada
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  • Ian F. Parney,

    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Oncology, Calgary, Alberta, Canada
    3. Department of Clinical, Neurosciences, Calgary, Alberta, Canada
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  • Samuel Weiss

    Corresponding author
    1. Hotchkiss Brain Institute, Calgary, Alberta, Canada
    2. Department of Cell Biology and Anatomy, Calgary, Alberta, Canada
    • Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Room 2263, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1

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    • Telephone: 403-220-3994; Fax: 403-210-9382


  • Author contributions: J.J.P.K.: Conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; O.S.: Conception and design, collection and/or assembly of data, data analysis and interpretation; A.C.: Conception and design, data analysis and interpretation, manuscript writing; X.L., J.F.D.: Collection and/or assembly of data, data analysis and interpretation; B.S.: Collection and/or assembly of data; D.L.S., R.N.A.: Conception and design, data analysis and interpretation; P.F.: Conception and design, financial support, data analysis and interpretation; J.G.C.: Conception and design, financial support, administrative support, data analysis and interpretation; I.F.P.: Conception and design, provision of study material or patients, financial support, data analysis and interpretation; S.W.: Conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS April 23, 2009.

Abstract

Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation of human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural stem cells remain to be elucidated. We cultured cells isolated from gliomas, using the neurosphere culture system, to understand their growth requirements. Both CD133+ and CD133 adult GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor (EGF) and fibroblast growth factor-2 enhanced GBM BTSC survival, proliferation, and subsequent sphere size. Blockade of EGF receptor (EGFR) signaling reduced exogenous mitogen-independent GBM sphere growth. Implantation of as few as 10 exogenous mitogen-independent GBM BTSCs led to the formation of highly invasive intracranial tumors, which closely resembled human GBMs, in immunocompromised mice. These results demonstrate that exogenous mitogen independence, mediated in part through EGFR signaling, is one characteristic that distinguishes CD133+ and CD133 GBM BTSCs from neural stem cells. This novel experimental system will permit the elucidation of additional constitutively activated mechanisms that promote GBM BTSC survival, self-renewal, and proliferation. STEM CELLS 2009;27:1722–1733

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