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

Alexander Pietras; Loen M Hansford; A Sofie Johnsson; Esther Bridges; Jonas Sjölund; David Gisselsson; Matilda Rehn; Siv Beckman; Rosa Noguera; Samuel Navarro; Jörg Cammenga; Erik Fredlund; David R Kaplan; Sven Påhlman

doi:10.1073/pnas.0904606106

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

Alexander Pietras, Loen M Hansford, A Sofie Johnsson, Esther Bridges, Jonas Sjölund, David Gisselsson, Matilda Rehn, Siv Beckman, Rosa Noguera, Samuel Navarro, Jörg Cammenga, Erik Fredlund, David R Kaplan, Sven Påhlman

113 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	106
Udgave nummer	39
Sider (fra-til)	16805-10
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.0904606106
Status	Udgivet - 29 sep. 2009
Udgivet eksternt	Ja

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10.1073/pnas.0904606106

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Pietras, A., Hansford, L. M., Johnsson, A. S., Bridges, E., Sjölund, J., Gisselsson, D., Rehn, M., Beckman, S., Noguera, R., Navarro, S., Cammenga, J., Fredlund, E., Kaplan, D. R., & Påhlman, S. (2009). HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 106(39), 16805-10. https://doi.org/10.1073/pnas.0904606106

HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. / Pietras, Alexander; Hansford, Loen M; Johnsson, A Sofie et al.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 106, Nr. 39, 29.09.2009, s. 16805-10.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Pietras, A, Hansford, LM, Johnsson, AS, Bridges, E, Sjölund, J, Gisselsson, D, Rehn, M, Beckman, S, Noguera, R, Navarro, S, Cammenga, J, Fredlund, E, Kaplan, DR & Påhlman, S 2009, 'HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells', Proceedings of the National Academy of Sciences of the United States of America, bind 106, nr. 39, s. 16805-10. https://doi.org/10.1073/pnas.0904606106

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title = "HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells",

abstract = "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.",

keywords = "Animals, Basic Helix-Loop-Helix Transcription Factors/genetics, Cell Differentiation, Cell Hypoxia, Cell Line, Tumor, Down-Regulation, Female, Humans, Mice, Mice, Nude, Neural Crest/metabolism, Neuroblastoma/metabolism, Vascular Endothelial Growth Factors/genetics",

author = "Alexander Pietras and Hansford, {Loen M} and Johnsson, {A Sofie} and Esther Bridges and Jonas Sj{\"o}lund and David Gisselsson and Matilda Rehn and Siv Beckman and Rosa Noguera and Samuel Navarro and J{\"o}rg Cammenga and Erik Fredlund and Kaplan, {David R} and Sven P{\aa}hlman",

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T1 - HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

AU - Pietras, Alexander

AU - Hansford, Loen M

AU - Johnsson, A Sofie

AU - Bridges, Esther

AU - Sjölund, Jonas

AU - Gisselsson, David

AU - Rehn, Matilda

AU - Beckman, Siv

AU - Noguera, Rosa

AU - Navarro, Samuel

AU - Cammenga, Jörg

AU - Fredlund, Erik

AU - Kaplan, David R

AU - Påhlman, Sven

PY - 2009/9/29

Y1 - 2009/9/29

N2 - 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.

AB - 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.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Cell Differentiation

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - Down-Regulation

KW - Female

KW - Humans

KW - Mice

KW - Mice, Nude

KW - Neural Crest/metabolism

KW - Neuroblastoma/metabolism

KW - Vascular Endothelial Growth Factors/genetics

U2 - 10.1073/pnas.0904606106

DO - 10.1073/pnas.0904606106

M3 - Journal article

C2 - 19805377

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EP - 16810

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 39

ER -

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

Abstract

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