Artikel
The vascularization potential of endothelial-like cd105+ glioma stem cells
Suche in Medline nach
Autoren
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Ran Xu
- Charité - Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
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Rong Wang
- Memorial Sloan-Kettering Cancer Center, Berlin, Deutschland
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Peter Vajkoczy
- Charité - Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
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Viviane Tabar
- Memorial Sloan-Kettering Cancer Center, Berlin, Deutschland
| Veröffentlicht: | 18. Juni 2018 |
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Gliederung
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Objective: Glomeruloid bodies (GB) encompass a characteristic defining neuropathologic feature in glioblastoma multiforme (GBM). Recent studies have shed light on the role of glioma stem cells (GSC) that can give rise to endothelial and mural-like cells participating in angiogenesis and tumor vasculature. The aim of this study was to investigate the contribution of endothelial-like cd105-positive GSC to GB formation as well as their potential to acquire both endothelial and mesenchymal fates.
Methods: For phenotypic and genomic characterization of GB in human samples, parent tumor samples of patients diagnosed with GBM were analyzed via immunofluorescence (IF) triple-staining and FISH (n=12). Human primary cell lines GBM401 and GBM306 were exposed to mesenchymal and endothelial medium and FACS analysis and IF was performed for fate characteristics. For ex vivo experiments FACS-sorted cd105+ GCS were injected into human tumor explants (n=10) as well as zebrafish to characterize their vascularization potential. Finally, explants and cell lines were treated with Avastin and gamma-secretase inhibitor (RO4929097), followed by viability and proliferation assays, IF for endothelial and mesenchymal characteristics as well Western Blotting.
Results: In human GBM samples, cd105 (Endoglin) is most consistently expressed in GB amongst other vascular markers (cd31, cd34, colIV, PDGFRbeta). GSC can give rise to a cd105+ subpopulation that can transition into different phenotypes reminiscent of either endothelial or mesenchymal fates as demonstrated by FACS analysis and IF. This is further delineated by their capability to form vascular-like channels in vivo and GB-like structures ex vivo (co-labeling with vasculature of cd105+ GCS vs. cd105-GCS: 41.7% vs. 28.1%). Dual Notch and VEGF blockage decreases proliferation of cd105+ GSC in vitro as well EMT-like transition.
Conclusion: Cd105 positive GSC contribute to GB formation and can acquire both endothelial and mesenchymal fates. Dual VEGF and Notch blockade decreases EMT-like characteristics of GSC and interrups GB formation ex vivo, and hence, may represent a potential treatment avenue in altering EMT-like transition in GBM.
