Hypoxia is an important condition in the
tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to
hypoxia with
hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many
cancers in adults, but data on pediatric
tumors are scarce. Because, by immunohistochemistry, HIF-1alpha expression was readily detectable in 18 of 28 primary
Ewing's sarcoma family
tumors (ESFT), a group of highly malignant bone-associated
tumors in children and young adults, we studied the effect of
hypoxia on ESFT cell lines in vitro. Intriguingly, we found that
EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by
hypoxia in a HIF-1alpha-dependent manner.
Hypoxia modulated the
EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of
EWS-FLI1 and of
hypoxia were observed. Consistent with alterations in the expression of
metastasis-related genes,
hypoxia stimulated the invasiveness and soft
agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify
hypoxia as an important microenvironmental factor modulating
EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT.