Hypoxia and hypoxia-inducible factors in neuroblastoma

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Hypoxia
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Neovascularization, Pathologic / metabolism
  • Neuroblastoma / blood supply
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology*
  • Oxygen / metabolism
  • Treatment Outcome


  • Hypoxia-Inducible Factor 1
  • Oxygen