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

作者：Wu Megan; Guan Jennifer; Li Chris; Gunter Simon; Nusrat Labeeba; Ng Sheena; Dhand Karan; Morshead Cindi; Kim Albert; Das Sunit^*

来源：Oncotarget, 2017, 8(47): 82217-82230.

DOI：10.18632/oncotarget.19283

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

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.

• 出版日期2017-10-10