Open AccessHIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
Author(s) -
Alexander Pietras,
Loen M. Hansford,
Ann Johnsson,
Esther Bridges,
Jonas Sjölund,
David Gisselsson,
Matilda Rehn,
Siv Beckman,
Rosa Noguera,
Samuel Navarro,
Jörg Cammenga,
Erik Fredlund,
David R. Kaplan,
Sven Påhlman
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0904606106
Subject(s) - neuroblastoma , neural crest , biology , cancer research , angiogenesis , gene knockdown , tumor progression , pathology , endocrinology , microbiology and biotechnology , cell culture , embryo , medicine , cancer , genetics
High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha 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-2alpha-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-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.