Hypoxia and HIF1α Repress the Differentiative Effects of BMPs in High-Grade Glioma

DOI PDF Web Site Web Site Web Site 被引用文献3件
  • Francesca Pistollato
    Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
  • Hui-Ling Chen
    Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
  • Brian R. Rood
    Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
  • Hui-Zhen Zhang
    Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
  • Domenico D'Avella
    Department of Neurosurgery, University of Padova, Padova, Italy
  • Luca Denaro
    Department of Neurosurgery, University of Padova, Padova, Italy
  • Marina Gardiman
    Department of Pathology, University of Padova, Padova, Italy
  • Geertruy te Kronnie
    Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
  • Philip H. Schwartz
    Children's Hospital of Orange County Research Institute, Orange, California, USA, and University of California, Irvine, Irvine, California, USA
  • Elena Favaro
    Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy
  • Stefano Indraccolo
    Istituto Oncologico Veneto – IRCCS, Padova, Italy
  • Giuseppe Basso
    Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
  • David M. Panchision
    Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA

抄録

<jats:title>Abstract</jats:title> <jats:p>Hypoxia commonly occurs in solid tumors of the central nervous system (CNS) and often interferes with therapies designed to stop their growth. We found that pediatric high-grade glioma (HGG)-derived precursors showed greater expansion under lower oxygen tension, typical of solid tumors, than normal CNS precursors. Hypoxia inhibited p53 activation and subsequent astroglial differentiation of HGG precursors. Surprisingly, although HGG precursors generated endogenous bone morphogenetic protein (BMP) signaling that promoted mitotic arrest under high oxygen tension, this signaling was actively repressed by hypoxia. An acute increase in oxygen tension led to Smad activation within 30 minutes, even in the absence of exogenous BMP treatment. Treatment with BMPs further promoted astroglial differentiation or death of HGG precursors under high oxygen tension, but this effect was inhibited under hypoxic conditions. Silencing of hypoxia-inducible factor 1α (HIF1α) led to Smad activation even under hypoxic conditions, indicating that HIF1α is required for BMP repression. Conversely, BMP activation at high oxygen tension led to reciprocal degradation of HIF1α; this BMP-induced degradation was inhibited in low oxygen. These results show a novel, mutually antagonistic interaction of hypoxia-response and neural differentiation signals in HGG proliferation, and suggest differences between normal and HGG precursors that may be exploited for pediatric brain cancer therapy.</jats:p>

収録刊行物

  • Stem Cells

    Stem Cells 27 (1), 7-17, 2009-01-01

    Oxford University Press (OUP)

被引用文献 (3)*注記

もっと見る

問題の指摘

ページトップへ