CONICET | Buscador de Institutos y Recursos Humanos

Introduction: Glioblastoma multiforme (GBM) is the most common and deadliest malignant primary brain tumor. GBM appear to have a hierarchical organization suggestive of a stem cell foundation. Thus, the isolation and expansion of these putative cancer stem cells, harboring tumor-specific phenotypes, constitute a powerful model to study GBM biology. The endothelin system consists of a group of 3 peptides, EDN1, EDN2, and EDN3, a EDN-converting enzyme (ECE1) and 2 distinct but highly homologous receptors, EDNRA and EDNRB. This system is involved in processes that mediate tumorigenicity such as proliferation, cell survival, migration and angiogenesis. Methods: Glioma Stem Cell (GSC) lines were isolated from biopsies and expanded in adherent culture in the presence of basic fibroblast growth factor and epidermal growth factor. Differentiation was achieved by the addition of BMP-4, and the neurotrophic factors: GDNF and BDNF. mRNA levels were measured by StepOne Real-Time PCR system. Results: To evaluate the potential role of the endothelin system in GSCs we determined the mRNA levels of the components of the endothelin axis in five GSC lines. We find that EDNRB transcripts are robustly expressed, while EDNRA are barely detectable in all tested cell lines. qPCR analysis revealed that EDN1 mRNA is highly expressed in GSC lines and markedly and progressively induced upon differentiation onset either by BMP-4 or serum. Importantly, in all cases we observed that after 14 days of GSCs differentiation, all components of this system were up-regulated. Conclusion: The present findings demonstrate that GSCs robustly express EDN1 and EDNRB at the undifferentiated and differentiated stages. It is tempting to speculate that these peptides would be necessary to sustainably maintain processes such as, endothelial cell proliferation, migration and invasion among others required for tumor progression.

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