Abstract
Abstract Neuroblastomas are the most common extracranial solid tumors in children. Neuroblastomas derive from neural crest stem cells blocked at different stages of the sympathetic nervous system development. Neuroblastomas display a variety of histological features that range from undifferentiated tumors in patients with poor outcome to those containing differentiated cell types which show a better prognosis. Hypoxia has been linked to tumor progression and increased malignancy. Like the most common malignant solid tumors, neuroblastomas contain zones of chronic or acute hypoxia reflecting poor oxygenation. Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of therapies. Differentiation is a key feature in pathologic classification and prognosis of neuroblastomas. The present study focuses on how intermittent hypoxia (IH) modulates the differentiation of neuroblastoma cells. IH-conditioned cells were derived by exposing tumor cells to 10 repeated cycles of hypoxia followed by reoxygenation. We found IH-induced changes in the expression of dedifferentiation markers and genes associated with neural crest-like phenotype in human neuroblastoma cells. The protein levels of HIF-1α, HIF-2α, tyrosine hydroxylase and c-kit were found upregulated in IH-conditioned human neuroblastoma cells as determined by western blotting. Similarly the expression of genes of neuronal crest phenotypic markers Oct-4, Notch-1and angiogenic molecule VEGF was found increased in IH-conditioned neuroblastoma cells. Expression of the cancer stem cell marker CD133 was also found increased in IH-conditioned neuroblastoma cells as evaluated by immunoflorescence analysis. Parallel studies were also performed in neuroblastoma cells exposed to hypoxia for 24h. It has been observed that IH-conditioned neuroblastoma cells exhibit increased expression of the proteins of dedifferentiation markers and genes associated with neural crest-like phenotype compared with neuroblastoma cells exposed to hypoxia for 24h. We cultured neuroblastoma cells, exposed the cells to defined doses of retinoic acid and studied neurite extension. A decrease in the levels of HIF-1α, and neuronal differentiation marker NF-M protein was observed in hypoxic neuroblastoma cells treated with retinoic acid. IH-conditioned neuroblastoma cells showed significantly less neurite extensions when compared with parental cells indicating that IH may suppress the differentiation of neuroblastoma cells. Taken together, our data suggest that IH inhibits differentiation and facilitates stem cell-like characteristics in human neuroblastoma cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2011-2055
Published Version
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