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Antisecretory Factor Reduces Tumor Pressure and Exhibits Anti-Tumor Activity in Human Glioblastoma

ABSTRACT: Glioblastoma (GBM) is among the most aggressive cancers and progresses with developing high interstitial fluid pressure (IFP). Increased IFP is a barrier to drug uptake, but the relationship between mechanical/osmotic stresses and tumor biology remains unclear. Blocking shrinkage-sensitive sodium-potassium-chloride co-transporter 1 (NKKC1) with its inhibitor bumetanide hinders proliferation and invasion of GBM cells. However, its clinical application is limited by poor brain penetration and adverse-effects. We found that compression promotes GBM cell proliferation, an effect antagonized by either bumetanide or antisecretory factor (AF), an antisecretory protein with a proved safety in humans. AF and bumetanide inhibited osmotic adaptation of cultured GBM cells in a similar manner. Using a telemetry-based approach, AF administration reduced IFP in patient-derived GBM xenografts, decreased tumor growth, increased cellular uptake of chemotherapeutics, and promoted temozolomide-sensitivity in GBM xenografts. In conclusion, AF therapy represents a novel pressure-reducing strategy with anti-tumor activity to safely improve the outcome of GBM patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81473 | GEO | 2017/05/01

SECONDARY ACCESSION(S): PRJNA321735

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.

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Antisecretory Factor Reduces Tumor Pressure and Exhibits Anti-Tumor Activity in Human Glioblastoma

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