Artikel
Mesenchymal stem-like cells in malignant gliomas represent a hypoxia-resistant subpopulation
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Veröffentlicht: | 28. April 2011 |
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Gliederung
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Objective: Enhanced proliferation, metabolic stress, necrosis and hypoxia are hallmarks of malignant gliomas. Emerging data suggest that malignant gliomas consist of diverse cell identities that produce a broad variety of factors in order to escape cell death through the loss of oxygenation, such as hypoxia-inducible factors (HIF1, HIF2) and erythropoietin (EPO) / erythropoietin receptor (EPO-R). In this study we isolated mesenchymal progenitor cells out of human glioblastoma specimen and compared the expression profile of hypoxia-related factors as well as the migration and proliferation capacity under normoxic and hypoxic conditions with malignant glioma cells.
Methods: The expression of HIF1, HIF2, EPO, EPO-R and VEGF were investigated in mesenchymal progenitor cells isolated from glioblastoma, as well as in glioma cell lines under normoxic and hypoxic conditions by RT-PCR. Furthermore, we characterized their hypoxia-induced migratory and proliferation behavior using the spheroid-based migration assay on laminin and proliferation assays.
Results: The expression of HIF2, EPO, EPO-R and VEGF increased under hypoxic conditions in glioma cell lines and mesenchymal progenitor cells. HIF1 was detected heterogeneously without a significant upregulation under hypoxia. Hypoxic conditions showed a pro-migratory effect on glioma cells lines, which is reduced in mesenchymal progenitor cells. In addition, the hypoxia-induced upregulation of hypoxia-related factors was only conducive to the proliferation of mesenchymal progenitor cells. In contrast the glioma cell lines showed decreased proliferation under hypoxia.
Conclusions: Expression of the hypoxia-related factors EPO, EPO-R and VEGF is not only limited to glioma cell lines but is mainly upregulated in glioma-isolated mesenchymal progenitor cells. Furthermore, our results suggest that different cells identities within a brain tumor show different responses to hypoxia in their proliferation and migration capacity.