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

Adgang til dokumentet

10.1073/pnas.0904606106

Citationsformater

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

@article{b15bff236eac45c3b7d9094ee2385fc6,

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",

year = "2009",

month = sep,

day = "29",

doi = "10.1073/pnas.0904606106",

language = "English",

volume = "106",

pages = "16805--10",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "The National Academy of Sciences of the United States of America",

number = "39",

}

TY - JOUR

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

SN - 0027-8424

VL - 106

SP - 16805

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

Adgang til dokumentet

Fingeraftryk

Citationsformater