Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CGNotch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66: 7445-7452

Johns Hopkins University, Baltimore, Maryland, United States
Cancer Research (Impact Factor: 9.33). 09/2006; 66(15):7445-52. DOI: 10.1158/0008-5472.CAN-06-0858
Source: PubMed


The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of gamma-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway.

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Available from: Charles G Eberhart
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    • "It was demonstrated that the activation of the Notch signaling pathway is characteristic to CD133 cells-positive in embryonic brain tumors. Inhibiting the signaling pathways leads to a decrease in the number of CD133 (+) cells with stem-like phenotype [22] [28]]. The best described is miR-21, which controls cell proliferation and survival, as well as let-7, an miR that is involved in the pathogenesis of breast cancer and in stem non-stem transition. "

    Full-text · Dataset · Jan 2015
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    • "In medulloblastomas, upregulated levels of Notch2 and its downstream targets have been linked with poor survival (Purow et al. 2005). Furthermore, Fan et al. (2006) demonstrated that Notch inhibition in medulloblastomas cells prompted differentiation and indicated a reduction in CD133 ? cell frequency and HES1 expression. "
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    • "Hes1 shRNA) or drug treatment (e.g., γ-secretase inhibitor) in pancreatic cancer decreased cancer stem cell population and tumorsphere formation (Abel et al., 2014). In addition, the inhibition of Notch signaling by treatment with GSI-18 (γ-secretase inhibitor) depleted the stem cell-like subpopulation derived from medulloblastoma cell lines and abolished xenograft formation (Fan et al., 2006). By contrast, the activation of the Notch signaling pathway with DSL peptide stimulated tumorsphere formation and increased cancer stem cell population (Abel et al., 2014). "
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