Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma.
We present evidence that in neuroblastoma, a pediatric malignancy of embryonal sympathetic origin, hypoxia, underlies a phenotypic switch from a primitive neuronal to a chromaffin cell type. This conclusion is based on morphological and molecular data on 116 clinical tumors and is supported by data on the phenotypic effects of hypoxia on neuroblastoma cell lines when studied in monolayer culture and as tumor xenografts. In the clinical material, extensive chromaffin features were seen in regions of chronic tumor hypoxia. This was the exclusive form of intra-tumoral maturation of stroma-poor tumors and was also seen in stroma-rich tumors, either exclusively or in combination with ganglion-like cells. In neuroblastoma cell lines, hypoxia induced changes in gene expression associated with the chromaffin features observed in vivo. We therefore propose tumor hypoxia as a major cue determining phenotype in sympathetic tumors of neuroblastic origin. Because it appears to be reversible upon reoxygenation in monolayer culture, we suggest the term metaplasia for the phenomenon.
Hedborg
Fredrik
F
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden. fredrik.hedborg@genpat.uu.se
Ullerås
Erik
E
Grimelius
Lars
L
Wassberg
Erik
E
Maxwell
Patrick H
PH
Hero
Barbara
B
Berthold
Frank
F
Schilling
Freimut
F
Harms
Dieter
D
Sandstedt
Bengt
B
Franklin
Gary
G
D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000235:genetics; D015687:Cell Hypoxia; D019439:Chromaffin Cells / Q000378:metabolism / Q000473:pathology*; D005333:Fetus; D019922:GAP-43 Protein / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008679:Metaplasia; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A
D043925:Angiogenesis Inducing Agents; D019922:GAP-43 Protein; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II