Role of Caveolin-1 in Hypoxia and Proneural to Mesenchymal Transition of Glioblastoma

Abstract

Glioblastomas (GBM), a grade IV astrocytoma, is the most common and aggressive primary brain tumors in adults, associated with short survival and uniformly fatal outcome irrespective of treatment. GBM is highly heterogeneous at both molecular and histological levels, including pseudopalisading necrosis, that make GBM most hypoxic and angiogenic tumor in nature. Recent transcriptomic profiling has identified 4 distinct subtypes of GBM based on specific gene expression pattern. Of these the mesenchymal GBM subtype was reported to be the most aggressive one with the worst clinical outcome. Caveolin-1 (Cav-1) is well known principle scaffolding protein in caveole that directly interacts with several signalling molecules and play crucial role in numerous signalling pathways. Over the past 10-15 years, Cav-1 has been found to have oncogenic and metastasis promoting roles in many aspects depending on the tumour type or tissue of interest. Within our project we investigated the role of a hypoxic microenvironment on Cav-1 expression and on mesenchymal and proneural markers by western blotting. Our preliminary data indicate that Cav-1 is elevated under hypoxia in a fraction of GBM cell lines. Upregulation of Cav-1 was confirmed in GBM patient samples around necrotic areas, however, expression pattern of Cav-1 showed inter- and intra-tumoral heterogeneity. Despite the heterogeneity, Cav-1 expression was found to be highly upregulated in hypoxic regions in most of GBM samples, indicating a possible connection between hypoxia and Cav-1 expression. TCGA patient data indicated a correlation of Cav-1 with mesenchymal markers and anti-correlation with proneural markers. Thus, we further investigated whether hypoxia induced a proneural to mesenchymal switch in GBM cell lines. Proneural markers PDGFRA and olig2 were downregulated under hypoxia, however no clear pattern for the mesenchymal markers YKL40, pSTAT3 and CD44 was observed. In conclusion, our results show that Cav-1 is upregulated under hypoxia in a subset of GBM, which parallels downregulation of proneural markers. Whether a mesenchymal shift is induced under hypoxia and whether this might be dependent on Cav-1 needs to be elucidated in future studies.