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

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Abstract
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.
Funding Information
  • Frank and Nancy Parsons Fund
  • Zickler Fund
  • Georgia Derrico and Rod Porter Fund for the CNMC/University of Padova Sister Program
  • Italian Association AIRC regional grant
  • FIRB grant
  • Italian Association for the Fight against Neuroblastoma
  • Italian Ministry of Health Oncology Program 2006
  • CNMC Research Advisory Council
  • CHOC Foundation for Children
  • CNMC Board of Visitors

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