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. 2018 May;372(2):269-275.
doi: 10.1007/s00441-017-2701-1. Epub 2017 Oct 14.

Hypoxia and Hypoxia-Inducible Factors in Neuroblastoma

Free PMC article

Hypoxia and Hypoxia-Inducible Factors in Neuroblastoma

Sven Påhlman et al. Cell Tissue Res. .
Free PMC article


Hypoxia (i.e., low oxygen levels) is a known feature of aggressive tumors. Cells, including tumor cells, respond to conditions of insufficient oxygen by activating a transcriptional program mainly driven by hypoxia-inducible factors (HIF)-1 and HIF-2. Both HIF-1α and HIF-2α expression levels have been shown to correlate to patient outcome in various tumor forms and in neuroblastoma, a solid childhood tumor of the sympathetic nervous system, in particular, HIF-2α marks a subpopulation of immature neural crest-like perivascularly located cells and associates with aggressive disease and distant metastasis. It has for long been recognized that the HIF-α subunits are oxygen-dependently regulated at the post-translational level, via ubiquitination and proteasomal degradation. Evidence of oxygen-independent mechanisms of regulation, transcriptional control of EPAS1/HIF2A and possible cytoplasmic activities of HIF-2α has also emerged during recent years. In this review, we discuss these non-conventional actions of HIF-2α, its putative role as a therapeutic target and the constraints it carries, as well as the importance of HIF-2 activity in a vascularized setting, the so-called pseudo-hypoxic state.

Keywords: Cancer stem cell; Hypoxia; Hypoxia-inducible factor; Neuroblastoma; Vascularization.


Fig. 1
Fig. 1
HIF-1α immunohistochemical staining of a necrotic area in a neuroblastoma specimen. Blood vessels can sufficiently supply approximately 10 cell layers with nutrients and oxygen. The hypoxia response machinery becomes activated when oxygen drops below physiological levels, which varies from tissue to tissue but is usually around 3–4% oxygen. N necrosis; BV blood vessel. Arrowheads indicate examples of cells with nuclear HIF-1α expression
Fig. 2
Fig. 2
Log2 mRNA expression of HIF1A, EPAS1/HIF2A, HIF3A and ARNT in 88 neuroblastomas, data derived from R2: Genomics Analysis and Visualization Platform (

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    1. Applebaum MA, Jha AR, Kao C, Hernandez KM, DeWane G, Salwen HR, Chlenski A, Dobratic M, Mariani CJ, Godley LA, Prabhakar N, White K, Stranger BE, Cohn SL. Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients. Oncotarget. 2016;7:76816–76826. doi: 10.18632/oncotarget.12713. - DOI - PMC - PubMed
    1. Beppu K, Nakamura K, Linehan WM, Rapisarda A, Thiele CJ. Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. Cancer Res. 2005;65:4775–4781. doi: 10.1158/0008-5472.CAN-04-3332. - DOI - PubMed
    1. Calvani M, Trisciuoglio D, Bergamaschi C, Shoemaker RH, Melillo G. Differential involvement of vascular endothelial growth factor in the survival of hypoxic colon cancer cells. Cancer Res. 2008;68:285–291. doi: 10.1158/0008-5472.CAN-07-5564. - DOI - PubMed
    1. Canete A, Navarro S, Bermudez J, Pellin A, Castel V, Llombart-Bosch A. Angiogenesis in neuroblastoma: relationship to survival and other prognostic factors in a cohort of neuroblastoma patients. J Clin Oncol. 2000;18:27–34. doi: 10.1200/JCO.2000.18.1.27. - DOI - PubMed
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