High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche.
High HIF-2alpha protein levels in the sympathetic nervous system-derived childhood tumour neuroblastoma as well as immature phenotype correlate to unfavourable outcome. Here we show that a small subset of perivascularly located, strongly HIF-2alpha-positive tumour cells (MYCN amplified) lacks expression of differentiation markers, but expresses neural crest and early sympathetic progenitor marker genes such as Notch-1, HES-1, c-Kit, dHAND, and vimentin. HIF-2alpha- and CD68-positive tumour-associated macrophages were frequently found close to the immature and HIF-2alpha-positive neuroblastoma cells and as VEGF levels are high in the perivascular niche, we hypothesize that neuroblastoma neural crest-like cells and macrophages cooperate to facilitate angiogenesis and thereby contribute to the aggressive neuroblastoma phenotype.
Pietras
A
A
Center for Molecular Pathology, Department of Laboratory Medicine, CREATE Health, Lund University, University Hospital MAS, Malmö, Sweden.
Gisselsson
D
D
Ora
I
I
Noguera
R
R
Beckman
S
S
Navarro
S
S
Påhlman
S
S
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D006801:Humans; D008264:Macrophages / Q000473:pathology; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009432:Neural Crest / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C459801:MYCN protein, human; C467484:VEGFA protein, human