Identification of human brain tumor initiating cells

The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada.
Nature (Impact Factor: 41.46). 12/2004; 432(7015):396-401. DOI: 10.1038/nature03128
Source: PubMed


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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    • "Recent evidence suggests that tumors arise from a small subpopulation of primary cells known as cancer stem cells (CSCs) or tumor initiating cells[1], which are capable of generating heterogeneous tumor cell populations[2]. Since the first identification of cancer stem cells in acute myelogenous leukemia (AML)[3], these cells have been identified and described in several solid and nonsolid malignancies including melanoma4567891011. CSCs have been proposed to originate either from malignant transformation of normal somatic tissue stem cells or progenitor cells[12]. "
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    ABSTRACT: Significance: The existence of cancer stem cells (CSCs) in many cancers including melanoma and their resistance to conventional regimens of cancer therapy results in post treatment relapse and metastasis of cancer, so targeting the CSC population is the novel goal of several researches. CSC targeted DC based immunotherapy also seems to be a potentially powerful choice for prevention or treatment of cancers. However there are rare studies concerning the use of DCs for targeting of CSCs.
    Full-text · Article · Jan 2016 · Cancer letters
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    • "However NSCs do not form tumors. By contrast, low numbers of GSCs are able to initiate tumors, the defining characteristic of cancer stem cells [7]. Tumors derived from GSCs faithfully mimic the phenotypic heterogeneity and invasiveness of human GBM tumors compared to tumors derived from serum-cultured cell lines [12] [13] [14]. "
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    ABSTRACT: Glioblastoma multiforme (GBM), a highly malignant brain tumor, accounts for half of all gliomas. Despite surgery, radiation and chemotherapy, the median survival is between 12-15 months. The poor prognosis is due to tumor recurrence attributed to chemoresistant glioma cancer stem cells (GSCs). Here we examined the effects of a novel compound NEO212, which is composed of two covalently conjugated anti-cancer compounds - temozolomide (TMZ) and perillyl alcohol (POH) on GSCs expressing either the proneural or mesenchymal gene signatures. These GSCs were obtained from patient-derived tumor tissue. Our findings demonstrate that NEO212 is 10 fold more cytotoxic to GSCs than TMZ (standard-of-care). Furthermore, NEO212 is effective against both proneural and clinically aggressive mesenchymal GSC subtypes. The mechanism of NEO212 mediated-cytotoxicity is through double strand DNA breaks and apoptosis. In vivo studies show that NEO212 significantly delays tumor growth of both proneural and mesenchymal tumor stem cell populations. Patient-derived GSCs and tumors derived from these cells are highly reflective of the heterogeneity in human GBM. The efficacy of NEO212 against both GSC subtypes indicates that NEO212 has great clinical potential to effectively target GBM.
    Full-text · Article · Dec 2015 · Cancer letters
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    • "Among these genes, nestin is relatively specific marker of brain CSCs [12], whereas Olig2 and Sox2 are not only widely accepted as CSCs markers of epithelial malignancies, but also considered to be essential for glioblastoma propagation [13]. As shown in Figure 1B, tumor ved GSCs might have more invasive and migrating capabilities. "
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    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.
    Full-text · Article · Jun 2015 · American Journal of Translational Research
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