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.
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ABSTRACT: A novel anticancer agent was constructed by fusing a gene encoding the scFV that targets both glycosylated and unglycosylated forms of CD133 to a gene fragment encoding deimmunized PE38KDEL. The resulting fusion protein, dCD133KDEL, was studied to determine its ability to bind and kill tumor-initiating cells in vitro and in vivo. The anti-CD133 scFV selectively bound HEK293 cells transfected with the CD133 receptor gene. Time course viability studies showed that dCD133KDEL selectively inhibited NA-SCC and UMSCC-11B, 2 head and neck squamous cell carcinomas that contain a CD133 expressing subpopulation. Importantly, the drug did not inhibit the viability of hematopoietic lineages measured by long-term culture-initiating cell and colony-forming assays from sorted human CD34+ progenitor cells. In addition to in vitro studies, in vivo tumor initiation experiments confirmed that CD133-sorted cells implanted into the flanks of nude mice grew faster and larger than unsorted cells. In contrast, cells that were pretreated with dCD133KDEL before implantation showed the slowest and lowest incidence of tumors. Furthermore, UMSCC-11B-luc tumors treated with multiple intratumoral injections of dCD133KDEL showed marked growth inhibition, leading to complete degradation of the tumors that was not observed with an irrelevant control-targeted toxin. Experiments in immunocompetent mice showed that toxin deimmunization resulted in a 90% reduction in circulating antitoxin levels. These studies show that dCD133KDEL is a novel anticancer agent effective at inhibiting cell proliferation, tumor initiation, and eliminating established tumors by targeting the CD133 subpopulation. This agent shows significant promise for potential development as a clinically useful therapy.Molecular Cancer Therapeutics 08/2011; 10(10):1829-38. · 5.60 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; · 5.64 Impact Factor
- 09/2011; , ISBN: 978-953-307-736-9