Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors.
Glioblastoma multiforme (GBM) remains refractory to conventional therapy. CD133+ GBM cells have been recently isolated and characterized as chemo-/radio-resistant tumor-initiating cells and are hypothesized to be responsible for post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM cells that resist treatment, we isolated CD133+ GBM cells from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ GBM cells sorted from the CD133+ GBM spheres express SOX2 and CD44 and are capable of clonal self-renewal and dividing to produce fast-growing CD133- progeny, which form the major cell population within GBM spheres. Intracranial injection of purified CD133+, not CD133- GBM daughter cells, can lead to the development of YKL-40+ infiltrating tumors that display hypervascularity and pseudopalisading necrosis-like features in mouse brain. The molecular profile of purified CD133+ GBM cells revealed characteristics of neuroectoderm-like cells, expressing both radial glial and neural crest cell developmental genes, and portraying a slow-growing, non-differentiated, polarized/migratory, astrogliogenic, and chondrogenic phenotype. These data suggest that at least a subset of treated and recurrent GBM tumors may be seeded by CD133+ GBM cells with neural and mesenchymal properties. The data also imply that CD133+ GBM cells may be clinically indolent/quiescent prior to undergoing proliferative cell division (PCD) to produce CD133- GBM effector progeny. Identifying intrinsic and extrinsic cues, which promote CD133+ GBM cell self-renewal and PCD to support ongoing tumor regeneration may highlight novel therapeutic strategies to greatly diminish the recurrence rate of GBM.
Liu
Qinghai
Q
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Factor Building, Rm 13-260, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Nguyen
David H
DH
Dong
Qinghua
Q
Shitaku
Peter
P
Chung
Kenneth
K
Liu
On Ying
OY
Tso
Jonathan L
JL
Liu
Jason Y
JY
Konkankit
Veerauo
V
Cloughesy
Timothy F
TF
Mischel
Paul S
PS
Lane
Timothy F
TF
Liau
Linda M
LM
Nelson
Stanley F
SF
Tso
Cho-Lea
CL
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000473:pathology*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics*; D018874:Spheroids, Cellular / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse