Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.

• Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Pediatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Pediatrics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Non-U.S. Gov't

Support

Phenotype

Chromaffin : cytology

Paraganglia

Oxygen : metabolism

Neuropeptide Y : genetics

Neuroblastoma

Neural Crest : cytology

Experimental

Neoplasms

Nude

Mice

Lymphokines : genetics

Insulin-Like Growth Factor II : genetics

Human

Helix-Loop-Helix Motifs

Hela Cells

Trans-Activators : genetics

Trans-Activators : metabolism

Transcription Factors : genetics

Transcription Factors : metabolism

Heterologous

Transplantation

Tumor Cells

Cultured

Tyrosine 3-Monooxygenase : genetics

Sympathetic Nervous System : metabolism

Gene Expression

Female

Endothelial Growth Factors : genetics

Down-Regulation

DNA-Binding Proteins : genetics

Cell Hypoxia

Biological Markers

Animal

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