Identification of CD133(-)/telomerase(low) progenitor cells in glioblastoma-derived cancer stem cell lines.
ABSTRACT Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. The CSC hypothesis implies that tumors are maintained by a rare subpopulation of CSC that gives rise to rapidly proliferating progenitor cells. Although the presence of progenitor cells is crucial for the CSC hypothesis, progenitor cells derived from GBM CSC are yet uncharacterized. We analyzed human CD133(+) CSC lines that were directly derived from CD133(+) primary astrocytic GBM. In these CSC lines, CD133(+)/telomerase(high) CSC give rise to non-tumorigenic, CD133(-)/telomerase(low) progenitor cells. The proliferation of the progenitor cell population results in significant telomere shortening as compared to the CD133(+) compartment comprising CSC. The average difference in telomere length as determined by a modified multi-color flow fluorescent in situ hybridization was 320 bp corresponding to 4-8 cell divisions. Taken together, we demonstrate that CD133(+) primary astrocytic GBM comprise proliferating, CD133(-)/telomerase(low) progenitor cell population characterized by low telomerase activity and shortened telomeres as compared to CSC.
- SourceAvailable from: Felix M Mottaghy
[Show abstract] [Hide abstract]
- "Human primary GBM cells R8 (CD133−), R18 and R28 (CD133+) were kindly provided by Dr. Dagmar Beier (Department of Neurology, University Aachen, RWTH, Germany). The procedure of generation of primary GBM cells and histological classification were described by Beier et al [32, 42]. GBM cells were cultured in stem cell-permissive DMEM/F12 medium (PAN, Germany) supplemented with human recombinant epidermal growth factor, human recombinant basic fibroblast growth factor (both PeproTech, Rocky Hill, New Jersey, USA) and human leukemia inhibitory factor (Active Bioscence, Germany), 20 ng/mL of each, and 2% B27 (Gibco, Life Technologies, Carlsbad, California, USA) in non-tissue treated plates. "
ABSTRACT: The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activated glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4’-thio-2’-deoxyuridine ([I-125]ITdU) leads to a fatal nanoirradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.Oncotarget 06/2014; 5(14):5483-5493. DOI:10.18632/oncotarget.2123 · 6.36 Impact Factor
Molecular Targets of CNS Tumors, 09/2011; , ISBN: 978-953-307-736-9
- "There is general consensus that CD133 + /telomerase High CSC gives rise to CD133 -/telomerase Low progenitor cells. It is the proliferation of these progenitor cells that populate and makes up the tumor mass (Beier et al., 2011). Moreover, it has been shown that differentiated tumor cells are more susceptible to chemotherapy and radiation treatment, and are eliminated from the tumor mass. "
- [Show abstract] [Hide abstract]
ABSTRACT: Glioblastoma multiforme (GBM) is the most lethal type of brain tumour in the adult humans. The cancer-initiating cell (CIC) hypothesis supports the notion that failures in current approaches to GBM treatment might be attributed to the survival of the CIC subpopulation. Recent evidence shows the idea that using CIC-enriched cell lines derived from human GBM as new targets for drug discovery programs, may improve the chance of successfully translating the basic research findings into clinical trials. Although this approach appears promising, many important biological and technical issues (characterization of functional CIC markers, inter- and intra-tumoral CIC heterogeneity, and isolation and maintenance inconsistency) need to be resolved.Stem cell reviews 06/2011; 8(1):288-98. DOI:10.1007/s12015-011-9283-1 · 2.77 Impact Factor