Oncotarget

Research Papers:

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

Megan Wu, Jennifer Guan, Chris Li, Simon Gunter, Labeeba Nusrat, Sheena Ng, Karan Dhand, Cindi Morshead, Albert Kim and Sunit Das _

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Oncotarget. 2017; 8:82217-82230. https://doi.org/10.18632/oncotarget.19283

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Abstract

Megan Wu1, Jennifer Guan1, Chris Li1, Simon Gunter2, Labeeba Nusrat3, Sheena Ng1, Karan Dhand1, Cindi Morshead3, Albert Kim2 and Sunit Das1,4

1Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids, University of Toronto, Toronto, Canada

2Department of Neurosurgery and Cell Biology, Washington University, St. Louis, MO, USA

3McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Canada

4Division of Neurosurgery and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada

Correspondence to:

Sunit Das, email: [email protected]

Keywords: glioblastoma, cancer stem cells, cyclooxygenase, prostaglandin E2, Wnt

Received: March 13, 2017     Accepted: June 16, 2017     Published: July 17, 2017

ABSTRACT

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.


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