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Phenotypic persistence after reoxygenation of hypoxic neuroblastoma cells
Author(s) -
Holmquist Linda,
Jögi Annika,
Påhlman Sven
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21024
Subject(s) - neuroblastoma , hypoxia (environmental) , phenotype , downregulation and upregulation , biology , neural crest , cancer research , cell culture , transcription factor , gene , endocrinology , medicine , pathology , chemistry , genetics , oxygen , organic chemistry
Fast‐growing solid tumors are usually insufficiently vascularized, leading to areas with necrosis and/or poorly oxygenated cells. Tumor cells adapt to acute hypoxic stress. Central to this adaptation are the hypoxia‐inducible transcription factors (HIFs), which are degraded at normoxic but become stabilized at hypoxic conditions. Hypoxic (1% O 2 ) neuroblastoma cells downregulate sympathetic nervous system marker genes, whereas neural crest cell markers are upregulated, suggesting that hypoxic tumor cells adopt a less mature phenotype, which in the clinical setting would translate to more aggressive tumors with increased metastatic potential. Here, we compared gene expression patterns in neuroblastoma cells grown at 1%, 5% (a physiologic oxygen level) and 21% O 2 . At 5% O 2 , cells developed a weak hypoxic phenotype and HIF‐2 α, but not HIF‐1 α, was acutely stabilized. At 1% O 2 , HIF‐2 α protein remained present in long‐term cultures, while HIF‐1 α was present only transiently. The stability of the hypoxia‐induced dedifferentiated phenotype in cells acutely reoxygenated at either 21% or 5% O 2 persisted for at least 24 hr. Genes associated with a differentiated state, like NPY , ChrA and ChrB , were still downregulated and hypoxia‐induced genes, like TH and Id2 , remained upregulated. Thus, if these culture conditions are viewed as models for acute reoxygenation of metastasizing hypoxic tumor cells, our data suggest that an aggressive hypoxic phenotype persists for 24 hr or more, which might be long enough for the cells to be able to home to secondary sites, in part as a consequence of their immature hypoxic characteristics. © 2005 Wiley‐Liss, Inc.

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