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Oncogene. 2018 Feb 22;37(8):1107-1118. doi: 10.1038/onc.2017.404. Epub 2017 Nov 20.

Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia.

Author information

1
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
2
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
3
Department of Biology, Dartmouth College, Hanover, NH, USA.
4
Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
5
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
6
Departments of Medicine and Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Abstract

High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. 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 hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1α levels are greatly increased in glioma stem-like cells. Increased HIF-1α activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia-mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100β-v-erbB/p53-/- glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs.

PMID:
29155422
PMCID:
PMC5851110
DOI:
10.1038/onc.2017.404
[Indexed for MEDLINE]
Free PMC Article

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