Abstract
Glioblastoma are rapidly proliferating brain tumors in which hypoxia is readily recognizable, as indicated by focal or extensive necrosis and vascular proliferation, two independent diagnostic criteria for glioblastoma. Gene expression profiling of glioblastoma revealed a gene expression signature associated with hypoxia-regulated genes. The correlated gene set emerging from unsupervised analysis comprised known hypoxia-inducible genes involved in angiogenesis and inflammation such as VEGF and BIRC3, respectively. The relationship between hypoxia-modulated angiogenic genes and inflammatory genes was associated with outcome in our cohort of glioblastoma patients treated within prospective clinical trials of combined chemoradiotherapy. The hypoxia regulation of several new genes comprised in this cluster including ZNF395, TNFAIP3, and TREM1 was experimentally confirmed in glioma cell lines and primary monocytes exposed to hypoxia in vitro. Interestingly, the cluster seems to characterize differential response of tumor cells, stromal cells and the macrophage/microglia compartment to hypoxic conditions. Most genes classically associated with the inflammatory compartment are part of the NF-kappaB signaling pathway including TNFAIP3 and BIRC3 that have been shown to be involved in resistance to chemotherapy.Our results associate hypoxia-driven tumor response with inflammation in glioblastoma, hence underlining the importance of tumor-host interaction involving the inflammatory compartment.
Highlights
Maintenance of oxygen homeostasis is critical for cell survival
Unsupervised analysis of our gene expression data-set derived from 80 glioblastoma and 4 non-tumoral brain tissues identified stable gene clusters that were associated with known biological processes, including a cluster characterized by hypoxia-induced genes as shown in Figure 1, Table 1
The hypoxia cluster drew our attention, when we found that the second principle component (PC) of this cluster was strongly associated with survival (p = 0.0015; HR, 1.73; 95% CI, 1.23 to 2.43; multivariate analysis including age, treatment, MGMT-methylation status [a predictive factor for benefit from temozolomide treatment [11]]), while the 1st PC, as well as the mean expression of the cluster, had no prognostic value in our cohort of patients
Summary
Hypoxia is a common condition in cancer tissue due to rapid tumor growth, accompanied by inadequate angiogenesis with formation of structurally aberrant, leaky blood vessels with poor blood flow and formation of edema. Such aberrant vascular proliferation characterized by glomeruloid and garland-like patterns are a hallmark of glioblastoma [1], the most malignant primary brain tumor. Hypoxia-regulated genes, mediating adaptive physiologic changes, include genes regulating the glycolytic pathway and blood-vessel formation, and genes encoding chemotactic molecules such as CCL2, IL8 and VEGF [2] In cancer, such changes are associated with recruitment of macrophages along a hypoxia-mediated chemotactic gradient. Tumor hypoxia is associated with aggressive tumor behavior and worse outcome in many cancers and its role in driving tumor malignancy and resistance to therapy is receiving increased attention
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