Cancer Stem Cells

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Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens†‡

  1. John J. P. Kelly1,2,
  2. Owen Stechishin1,2,
  3. Andrew Chojnacki1,2,
  4. Xueqing Lun3,
  5. Beichen Sun3,
  6. Donna L. Senger3,4,
  7. Peter Forsyth1,3,4,5,
  8. Roland N. Auer1,5,6,
  9. Jeff F. Dunn1,7,
  10. J. Gregory Cairncross1,4,5,
  11. Ian F. Parney1,4,5,
  12. Samuel Weiss1,2,§,*

Article first published online: 23 APR 2009

DOI: 10.1002/stem.98

Issue

STEM CELLS

STEM CELLS

Volume 27, Issue 8, pages 1722–1733, August 2009

Additional Information

How to Cite

Kelly, J. J. P., Stechishin, O., Chojnacki, A., Lun, X., Sun, B., Senger, D. L., Forsyth, P., Auer, R. N., Dunn, J. F., Cairncross, J. G., Parney, I. F. and Weiss, S. (2009), Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens. STEM CELLS, 27: 1722–1733. doi: 10.1002/stem.98

Author Information

  1. 1

    Hotchkiss Brain Institute, Calgary, Alberta, Canada

  2. 2

    Department of Cell Biology and Anatomy, Calgary, Alberta, Canada

  3. 3

    Clark Smith Integrative Brain Tumor Research Center and Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada

  4. 4

    Department of Oncology, Calgary, Alberta, Canada

  5. 5

    Department of Clinical, Neurosciences, Calgary, Alberta, Canada

  6. 6

    Department of Pathology and Laboratory Medicine, Calgary, Alberta, Canada

  7. 7

    Department of Diagnostic Imaging, University of Calgary, Calgary, Alberta, Canada

  1. §

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

*Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Room 2263, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1

  1. †

    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.

  2. ‡

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

Publication History

  1. Issue published online: 3 AUG 2009
  2. Article first published online: 23 APR 2009
  3. Accepted manuscript online: 23 APR 2009 12:00AM EST
  4. Manuscript Accepted: 14 APR 2009
  5. Manuscript Received: 16 DEC 2008

Funded by

  • Canadian Institutes of Health Research
  • National Cancer Institute of Canada with funds from the Terry Fox Foundation
  • Alberta Cancer Foundation Chair in Brain Tumor Research
  • Natural Sciences and Engineering Research Council of Canada studentship
  • Alberta Heritage Foundation for Medical Research Clinical Fellowship, Clinical Investigator and Scientist Awards

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Keywords:

  • Neural stem cell;
  • Brain tumor stem cell;
  • Glioma;
  • Glioblastoma;
  • Mitogen

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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