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

// Megan Wu 1 , Jennifer Guan 1 , Chris Li 1 , Simon Gunter 2 , Labeeba Nusrat 3 , Sheena Ng 1 , Karan Dhand 1 , Cindi Morshead 3 , Albert Kim 2 and Sunit Das 1, 4 1 Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids, University of Toronto, Toronto, Canada 2 Department of Neurosurgery and Cell Biology, Washington University, St. Louis, MO, USA 3 McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Canada 4 Division of Neurosurgery and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada Correspondence to: Sunit Das, email: sunit.das@utoronto.ca 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.