Interaction of Hypoxia-Inducible Factor-1α and Notch Signaling Regulates Medulloblastoma Precursor Proliferation and Fate

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  • Francesca Pistollato
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
  • Elena Rampazzo
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
  • Luca Persano
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
  • Sara Abbadi
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
  • Chiara Frasson
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
  • Luca Denaro
    Department of Neurosurgery, University of Padova, Padova, Italy
  • Domenico D'Avella
    Department of Neurosurgery, University of Padova, Padova, Italy
  • David M. Panchision
    Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
  • Alessandro Della Puppa
    Department of Neurosurgery, University of Padova, Padova, Italy
  • Renato Scienza
    Department of Neurosurgery, University of Padova, Padova, Italy
  • Giuseppe Basso
    SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy

抄録

<jats:title>Abstract</jats:title> <jats:p>Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133+ and nestin+ precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.</jats:p>

収録刊行物

  • Stem Cells

    Stem Cells 28 (11), 1918-1929, 2010-11-01

    Oxford University Press (OUP)

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