期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 39, 页码 16805-16810出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904606106
关键词
differentiation; tumor stroma; HIF-1; hypoxia; sympathetic nervous system
资金
- Swedish Cancer Society
- Children's Cancer Foundation of Sweden
- Swedish Research Council
- Swedish Foundation for Strategic Research (SSF) Strategic Center for Translational Cancer Research-CREATE Health
- Gunnar Nilsson's Cancer Foundation
- Spanish Institute of Health Carlos III Grants Accion Transversal del Cancer [20080143, FIS PI06/1576, RETICS RD06/0020/0102]
High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.
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