Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens.
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.
Kelly
John J P
JJ
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Stechishin
Owen
O
Chojnacki
Andrew
A
Lun
Xueqing
X
Sun
Beichen
B
Senger
Donna L
DL
Forsyth
Peter
P
Auer
Roland N
RN
Dunn
Jeff F
JF
Cairncross
J Gregory
JG
Parney
Ian F
IF
Weiss
Samuel
S
D000071916:AC133 Antigen; D000293:Adolescent; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D008934:Mitogens; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse