Abstract
Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor—clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.
Highlights
GBM is the most frequently diagnosed brain tumor with a high probability of aggressive relapse [1,2]
Correlation of expression levels of individual genes. mRNA expression of hypoxia markers and Notch genes was analyzed in 35 GBMs by q-PCR
phosphoglycerate kinase 1 (PGK1), carbonic anhydrase 9 (CA9), vascular endothelial growth factor (VEGF), OPN and HIF-1α were upregulated in 83%, 77%, 74%, 71% and 54% tumors, respectively (S3 Table)
Summary
GBM is the most frequently diagnosed brain tumor with a high probability of aggressive relapse [1,2]. As a rapidly growing tumor, GBM is characterized by central necrotic regions surrounded by hypoxic cancer cells. This niche confers resistance to therapy and harbors self-renewing cells responsible for tumor progression/recurrence [7]. Hypoxia essentially stabilizes HIF-1α (hypoxia inducible factor-1α), enabling transcriptional response that facilitates cell survival under hypoxic stress [8,9]. Genes like phosphoglycerate kinase 1 (PGK1), glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and carbonic anhydrase 9 (CA9) are directly regulated by HIF-1α and control glycolysis, angiogenesis, cell invasion/migration, etc. These, as well as osteopontin (OPN), are accredited tumor hypoxia markers and potential therapeutic targets [9,11,12,13]
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