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

ABSTRACT 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, Sep 29, 2015
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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. "
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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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    ABSTRACT: Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.
    Cytotechnology 12/2014; 67(5). DOI:10.1007/s10616-014-9830-0 · 1.75 Impact Factor
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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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    ABSTRACT: The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
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