Stem cell signatures in glioma

Sammanfattning: Gliomas are the most common tumors of the central nervous system in adults. Glioblastoma, the most aggressive form, has a median survival of 15 months regardless of the standard treatment with surgery and temozolomide-based radiochemotherapy. Therefore, it is imperative to improve treatment options for patients with glioblastoma. It has been suggested that the putative tumor stem cells in brain tumors are responsible for glioma initiation, development and resistance to conventional therapy and therefore may be a potential target for novel therapy. By searching for stem cell gene expression signatures in human high-grade glioma cultures, two novel subsets (type A and type B) of glioblastoma cultures were identified with gene expression profiles similar to the recently described TCGA proneural/classical/neural and the mesenchymal subsets, respectively. The two subsets of cultures have different capacities in terms of tumorigenic potential, sphere forming ability and distinct tyrosine kinase inhibitor sensitivity profiles. The findings that the resistance of type A cultures to tyrosine kinase inhibitor mono-treatment is SOX2- dependent and can be overcome by a combination of treatments with PDGFR and IGF1-R inhibitors provide a novel strategy for tumor stem cell-targeting therapy. A set of markers defining neural stem cells and pluripotent embryonic stem cells were tested on a series of human glioma tissues. Results demonstrated that besides deregulated expression of neural and pluripotent stem cell regulatory proteins, highgrade gliomas also show expression of mesodermal- and endodermal-specific transcription factors together with neural proteins. In vivo xenograft experiments indicated that the presence of pluripotency markers is dependent on signals from the tumor microenvironment. An experimental mouse glioma model with human PDGFB overexpressed in astrocyte and astrocyte progenitor cells on a p53 null background was used for studying epigenetic changes in mouse brain tumors and in neural stem/progenitor cells during the pre-neoplastic stage. DNA hypomethylation and elevated Histone3 Lysine9 dimethylation (H3K9Me2) were detected not only in the tumors but also in samples of the adult frontal brain lateral ventricular wall (LVW) and in neurosphere cultures respectively, from the hGFAPpPDGFB/Trp53 null (B+p53-/-) brain during the preneoplastic stage. Thus, non-neoplastic but epigenetically disturbed LVW cells might be early targets of transformation in the development of glioblastoma. Taken together, this work provides some new insights into stem cell related mechanisms involved in glioma development. Therefore, targeting brain cancer stem cells presents a new and potentially more effective therapy for glioma.