Abstract 5009: Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation

Abstract

Abstract Glioblastoma, a type of high-grade glioma, is the most common and the most aggressive primary brain tumor of adults. The median survival is 12-15 months. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven at least partly by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a pathway dependent upon tumor hypoxia, a commonly found pathologic feature of GBM, that promotes self-renewal through the HIF1α-JAK1/2-STAT3 axis. Under hypoxic conditions, the expression of HIF1α is greatly increased in GBM stem-like cells leading to the activation of JAK1/2-STAT3 which mediates enhanced tumor stem-like cell self-renewal. Our data further demonstrate the importance of VEGF secretion for this pathway of hypoxia-mediated self-renewal. Using tumor stem-like cells derived from the S100β-v-erbB/p53-/- mouse model of spontaneous high-grade glioma, we have discovered that the activation of STAT3 through hypoxia-mediated VEGF secretion is required for self-renewal of glioma stem-like cells. Media conditioned by these S100β-v-erbB/p53-/- tumor sphere cells cultured under hypoxic conditions promoted self-renewal in S100β-v-erbB/p53-/- glioma stem-like cells and depletion of VEGF from this media was sufficient to inhibit STAT3 phosphorylation. Moreover, we have been able to identify two drugs: Brefeldin A and EHT-1864, that significantly inhibit VEGF secretion, decrease stem cell self-renewal, inhibit tumor growth, and increase the survival of mice allografted with S100β-v-erbB/p53-/- glioma stem-like cells. Cells treated with these drugs express molecular signatures that correlated strongly with the increased survival of GBM patients. These findings suggest a novel treatment strategy to inhibit hypoxia-mediated self-renewal of glioma stem-like cells in high-grade gliomas by targeting the secretion of extracellular, paracrine mediators of self-renewal. Citation Format: Damian A. Almiron Bonnin, Matthew C. Havrda, Huan Liu, Myung Chang Lee, Matthew H. Ung, Chao Cheng, Mark A. Israel. Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5009. doi:10.1158/1538-7445.AM2017-5009