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Oncotarget. 2017 Jul 17;8(47):82217-82230. doi: 10.18632/oncotarget.19283. eCollection 2017 Oct 10.

Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma.

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Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids, University of Toronto, Toronto, Canada.
Department of Neurosurgery and Cell Biology, Washington University, St. Louis, MO, USA.
McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Canada.
Division of Neurosurgery and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada.


Glioblastoma recurrence after aggressive therapy typically occurs within six months, and patients inevitably succumb to their disease. Tumor recurrence is driven by a subpopulation of cancer stem cells in glioblastoma (glioblastoma stem-like cells, GSCs), which exhibit resistance to cytotoxic therapies, compared to their non-stem-cell counterparts. Here, we show that the Cox-2 and Wnt signaling pathways are aberrantly activated in GSCs and interact to maintain the cancer stem cell identity. Cox-2 stimulates GSC self-renewal and proliferation through prostaglandin E2 (PGE2), which in turn activates the Wnt signaling pathway. Wnt signaling underlies PGE2-induced GSC self-renewal and independently directs GSC self-renewal and proliferation. Inhibition of PGE2 enhances the effect of temozolomide on GSCs, but affords only a modest survival advantage in a xenograft model in the setting of COX-independent Wnt activation. Our findings uncover an aberrant positive feedback interaction between the Cox-2/PGE2 and Wnt pathways that mediates the stem-like state in glioblastoma.


Wnt; cancer stem cells; cyclooxygenase; glioblastoma; prostaglandin E2

Conflict of interest statement

CONFLICTS OF INTEREST The authors have declared that no conflicts of interest exists.

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