Metabolic challenge of proneural glioblastoma cancer stem cell lines does not induce a mesenchymal transformation in vitro
The histologically defined tumor entity glioblastoma (GBM) comprises different molecular subgroups. On a transcriptional level, at least two subgroups were uniformly identified: proneural and mesenchymal GBM. Treatment of GBM with radiotherapy and anti angiogenic drugs may trigger molecular subtype transformation with proneural tumors shifting towards a mesenchymal phenotype. Because both treatment modalities also result in dramatic changes of the metabolic microenvironment of GBM, we hypothesized if the major determinants in local microenvironment hypoxia and (lactate) acidosis may induce consistent changes in the phenotype of primary glioblastoma stem cell lines in vitro. A panel of 5 different proneural GBM stem cell lines (GSC) lines was systematically challenged for 7 days with acidosis (pH 5.5 7.4) sodium lactate (0 60 mM) lactic acid (0 15 mM) or with 72 h hypoxia (2% oxygen) Acidosis significantly improved survival but inhibited proliferation of GSC lines. Sodium lactate inhibited proliferation without affecting survival. Neither acidosis nor sodium lactate did consistently change growth pattern or stem cell marker expression. Hypoxia and lactate induced a more proneural like phenotype with increased Olig2 and CD133 expression in 1 GSC line, but did not consistently alter marker expression in the other 4 GSC lines. None of the 5 GSC lines investigated showed changes indicative for a proneural to mesenchymal transformation towards a more malignant phenotype. Taken together, our data does not exclude the possibility that metabolic factors like lactate acidosis may induce a more mesenchymal phenotype. Nevertheless, data suggest that therapy induced metabolic changes in the microenvironment are likely not of crucial importance to our understanding of mesenchymal transformation after radio and anti angiogenic therapy for most GBM.