Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens
- 23 April 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in The International Journal of Cell Cloning
- Vol. 27 (8), 1722-1733
- https://doi.org/10.1002/stem.98
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. Disclosure of potential conflicts of interest is found at the end of this article.Keywords
Funding Information
- 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
This publication has 26 references indexed in Scilit:
- Distinctions between fetal and adult human platelet‐derived growth factor–responsive neural precursorsAnnals of Neurology, 2008
- CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular ProfilesCancer Research, 2007
- Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular ExtensionScience, 2007
- Identification of human brain tumour initiating cellsNature, 2004
- Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migrationNature, 2004
- Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brainNature Medicine, 2003
- EGF Converts Transit-Amplifying Neurogenic Precursors in the Adult Brain into Multipotent Stem CellsNeuron, 2002
- Establishment and Properties of a Growth Factor-Dependent, Perpetual Neural Stem Cell Line from the Human CNSExperimental Neurology, 2000
- Clonal and Population Analyses Demonstrate That an EGF-Responsive Mammalian Embryonic CNS Precursor Is a Stem CellDevelopmental Biology, 1996
- Generation of Neurons and Astrocytes from Isolated Cells of the Adult Mammalian Central Nervous SystemScience, 1992