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: Victor CK TseMolecular Targets of CNS Tumors, 09/2011; , ISBN: 978-953-307-736-9
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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. · 6.63 Impact Factor
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ABSTRACT: Despite decades of search for anticancer drugs targeting solid tumours, this group of diseases remains largely incurable, especially if in advanced, metastatic stage. In this review, we draw comparison between reprogramming and carcinogenesis, as well as between stem cells and cancer stem cells, focusing on changing garniture of adhesion molecules. Furthermore, we elaborate on the role of adhesion molecules in the regulation of (cancer) stem cells division (symmetric, or asymmetric), and in evolving interactions between cancer stem cells and extracellular matrix. Among other aspects, we analyze the role and changes of expression of key adhesion molecules as cancer progresses and metastases develop. Here the role of cadherins, integrins, as well as selected transcription factors like twist and snail is highlighted, not only in the regulation of epithelial-mesenchymal transition, but also in the avoidance of anoikis. Finally, we briefly discuss recent developments and new strategies targeting cancer stem cells, which focus on adhesion molecules or targeting tumour vasculature.Carcinogenesis 02/2014; · 5.27 Impact Factor