HIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

A Pietras, LM Hansford, AS Johnsson… - Proceedings of the …, 2009 - National Acad Sciences
A Pietras, LM Hansford, AS Johnsson, E Bridges, J Sjölund, D Gisselsson, M Rehn…
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
High hypoxia-inducible factor-2α (HIF-2α) protein levels predict poor outcome in
neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural
crest-like phenotype. Here, we identify HIF-2α as a marker of normoxic neural crest-like
neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows.
Knockdown of HIF-2α reduced VEGF expression and induced partial sympathetic neuronal
differentiation when these TICs were grown in vitro under stem cell-promoting conditions …
High hypoxia-inducible factor-2α (HIF-2α) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2α as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2α 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-2α-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-2α maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2α is an attractive target for neuroblastoma therapy.
National Acad Sciences