Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396-401
ABSTRACT The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.
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Article: Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396-401
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- "These stem cells have the capacity for selfperpetuation as well as to generate mature cells of specific tissue lineages (Bonnet and Dick, 1997; Kim et al., 2005; Singh et al., 2003; Vermeulen et al., 2008) and, in this respect, represent good candidates for therapeutic intervention. The importance of this population to brain tumor biology is underscored by the demonstration that cancer stem cells (CSCs) generate tumors following injection into immunocompromised mice with similar histologic and growth properties to the parental tumor (Galli et al., 2004; Singh et al., 2004; Taylor et al., 2005). In addition, these CSCs harbor unique responses to conventional therapeutic agents (Beier et al., 2011; Sakariassen et al., 2007), which have broad implications for the design of treatments aimed at eliminating the very cells that maintain and recapitulate the tumor . "
ABSTRACT: The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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- "Other authors have demonstrated that in vitro growth of GSCs represents a significant predictor of clinical outcome [Pallini et al., 2008; Zeppernick et al., 2008]. Although it has recently been demonstrated that GSCs have tumorigenic potential in addition to enhanced resistance mechanisms [Singh et al., 2004], the real link between the biological features of brain tumor stem cells and their clinical behavior has yet to be established. "
ABSTRACT: Recently, glioma stem cells have been identified as the main cause of glioma propagation and recurrence and a number of several cell markers have been indicated as putative GSC markers. In the present work, a retrospective study to evaluate the prognostic potential of ability to generate GSCs in our series of 15 glioblastoma patients is described. β-tubulin III, nestin, CD133, GFAP and SOX-2 marker expression, both in primary GBM cultures and in respective glioblastoma stem cells (GSCs), was evaluated by flow cytometric analysis. Our results demonstrated various expression levels of these markers in both cell cultures; of note, only those cells expressing SOX-2 at greater than 30% levels were able to produce in vitro neurospheres. Moreover, statistical analysis revealed that the GSCs generation negatively affected overall survival (OS) (p = 0.000) and progression-free survival (PFS) (p = 0.001). In addition, a very poor OS (p = 0.000) and PFS (p = 0.000) were observed among patients whose tumors expressed Ki67, evaluated by immunohistochemistry, and showed the ability to generate in vitro GSCs. Overall, the results suggest that in vitro GSCs generation associated to the expression of Ki67 and SOX-2 may be useful to identify patients at risk of disease progression. This article is protected by copyright. All rights reservedJournal of Cellular Biochemistry 01/2015; DOI:10.1002/jcb.25043 · 3.37 Impact Factor
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- "Among these genes, nestin is relatively specific marker of brain CSCs , whereas Olig2 and Sox2 are not only widely accepted as CSCs markers of epithelial malignancies, but also considered to be essential for glioblastoma propagation . As shown in Figure 1B, tumor ved GSCs might have more invasive and migrating capabilities. "
ABSTRACT: Invasion is one of the deadly characteristics of malignant glioma with unknown underlying cellular and molecular mechanisms. In the present study, we investigated the role of toll-like receptor 2 (TLR2) in the invasiveness of malignant glioma. We enriched glioma stem cells (GSCs) from mouse GL261 cell line by means of tumor sphere formation, and found that GSCs expressed a significantly higher level of TLR2 than committed GL261 cells at the levels of mRNA and protein. Stimulation with Pam3CSK4, a ligand of TLR2, significantly increased the migration and invasion capability of GSCs. Knockdown of TLR2 attenuated the stimulating effect of Pam3CSK4 and the invasion capability of GSCs. An orthotopic allograft tumor model showed that TLR2-knockdown decreased the invasion capability of GSCs and prolonged survival span of tumor-bearing mice. The expressions of matrix metalloproteinases 2, 9 (MMP2 and MMP9) by GSCs were enhanced by treatment of Pam3CSK4 and decreased by TLR2 knockdown, implying that MMP2 and MMP9 were involved in TLR2-mediated invasion of GSCs. Our findings indicate that the activation of TLR2 up-regulates MMPs to promote invasion of GSCs, and suggest that TLR2 might be a potential therapeutic target for treatment of glioma patients.American Journal of Translational Research 01/2015; 7(3):607-15. · 3.23 Impact Factor