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Microarray analysis of U87 Glioblastoma Multiforme cell line exposed to proton irradiation during acute hypoxia.

ABSTRACT: Glioblastoma multiforme (GBM), is the most malignant and common tumor among glial neoplasms. It is characterized by a peak of incidence between 45 and 70 years and a patient median survival time of 14.6 months. In addition, GBM undergoes malignant progression under hypoxic conditions that contributes to strong radioresistance and chemoresistance; alters the metabolism of the tumor cells; generates a strong genome instability, increases the angiogenesis, vasculogenesis, and contributes to the formation of the Cancer Stem Cells (CSCs) and the infamous Circulating Tumor Cells (CTCs) involved in metastasis formation. Moreover, GBMs have a poor prognosis due to treatment (such as surgical resection, conventional RT and chemotherapy) plan failures. In this sense, since standard GBM treatments are not effective, new promising strategies such as Proton Therapy (PT), are under investigation because supported by encouraging results. Considering these assumptions, the main aim of this study was to analyze GBM response to PT innovative treatment during induced acute hypoxia, by using a whole gene expression analysis. Thus, in this work we have reported in a descriptive way, the most statistically and biologically relevant pathways deregulated in U87 GBM cell line, according to specific PT plans during hypoxia condition, and in addition, some interesting biomarker networks were following discussed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162986 | GEO | 2021/05/05

REPOSITORIES: GEO

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Project description:Tumor hypoxia is linked to poor outcome for many cancers, but the underlying mechanisms and the environmental factors that initiate tumor hypoxia are poorly understood. Here, we tracked tumor hypoxia in glioblastoma (GBM), a highly malignant brain cancer, in immunocompetent mice with a sensitive fluorescent reporter combined with single cell transcriptomics. We found that hypoxic GBM cells are quiescent and display a mesenchymal transition, both linked to malignant potency. We also captured in vivo hypoxia gene signature, which is more represented in recurrent GBM and predicts worse outcome. Interestingly, hypoxic GBM cells is a diverse population, consisted of four subclusters, and enriched for immune pathways. Concordantly, our reporter highlighted a distinct geographic pattern of immune cells in hypoxic regions, with phagocytic tumor-associated macrophages (TAMs) and CD8+ cytotoxic T cells (CTLs) congregated in hypoxic cores confined by hypoxic GBM cells in pseudopalisading patterns. Mechanistically, this is a dynamic temporospatial process, requiring cytokine CCL8. Remarkably, the sequestered TAMs also experience hypoxia, and they are reprogrammed to an immunotolerant state by factors released from hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia. Attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion significantly decreased GBM hypoxia in well-established tumors. Unexpectedly, radiation therapy (XRT) greatly reduced tumor hypoxia, and when combined with evofosfamide, a prodrug activated by hypoxia, achieved enhanced efficacy in tumor shrinkage and eradication of hypoxic GBM population. Analyses of human patient GBM samples highlighted a connection of mesenchymal subtype, immune response, and tumor hypoxia, all contributing to poor survival. Altogether, our study revealed a reciprocal influence of anti-tumor immunity and tumor hypoxia, which has important ramification for prognosis and immunotherapy for GBM.

Dataset Information

Microarray analysis of U87 Glioblastoma Multiforme cell line exposed to proton irradiation during acute hypoxia.

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