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.

Nyckelord

Adult

Angiogenesis Inducing Agents/genetics

Cell Hypoxia

Chromaffin Cells/metabolism/*pathology

Fetus

GAP-43 Protein/genetics

Gene Expression Regulation; Neoplastic

Humans

In Situ Hybridization

Infant

Infant; Newborn

Insulin-Like Growth Factor II/genetics

Metaplasia

Neuroblastoma/genetics/*pathology

Neurons/metabolism/*pathology

Research Support; Non-U.S. Gov't

Tumor Cells; Cultured

Vascular Endothelial Growth Factor A

Publikations- och innehållstyp

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