Modulation of Angiogenic and Inflammatory Response in Glioblastoma by Hypoxia

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.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial

“…Based on a comprehensive analysis of PPN in human GBM and experimental models, it has been hypothesized that pseudopalisades comprise hypoxic tumor cells migrating away from dysfunctional vessels [2,28]. However, the presence of PPN does not directly correlate with hypoxia as suggested by gene expression profiles available for 50 patients of this cohort [21,22]. No correlation was observed with the previously identified hypoxia-induced gene expression signature, while the EGFR expression signature (G25) was significantly associated with the presence of PPN (p = 0.02).…”

High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

“…Inflammation has been shown to be critical for promoting apoptosis resistance, proliferation, invasion, metastasis and secretion of proangiogenic and immunosuppressive factors in tumors of different origins, including lung (Peebles et al, 2007), prostate (Stock et al, 2008), breast (Hu and Polyak, 2008), stomach (Correa and Houghton, 2007), pancreas (Chu et al, 2007), gut (Quante and Wang, 2008) and, of course, the brain (Murat et al, 2009;Paugh et al, 2009). Thus, it is easy to imagine how the brain parenchyma of an AD patient, which is rich in proinflammatory mediators, would be a good environment for the development and progression of brain tumors.…”

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

“…These studies revealed distinct phenotypic states or subtypes that stratify gliomas and resemble different glial lineages (1)(2)(3). Although immunological gene expression classifications have been associated with clinical outcomes and prognosis (4,5), precision immunotherapy will ultimately rely on manipulation of the T-cell population that infiltrates gliomas and its underlying repertoire of T-cell receptors (TCRs). However, the structure and intertumoral heterogeneity of the TIL population in gliomas has not been described.…”