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.
Highlights
Despite advances in therapy, outcomes for patients with glioblastoma remain dismal
As Cox-2 has been implicated as a mediator of the cancer stem cell phenotype in mouse glioblastoma, we sought to determine if it has an analogous role in the human disease
Analogous to gross tumor expression data from The Cancer Genome Atlas (TCGA), Cox-2 expression is higher in glioblastoma stem-like cells (GSCs) generated from high-grade gliomas than in GSCs generated from low-grade gliomas in culture
Summary
Outcomes for patients with glioblastoma remain dismal. Disease recurrence after surgery, radiation and chemotherapy, typically occurs within six months, and patients inevitably succumb to disease progression at just over one year [1]. Emerging recognition of the cellular heterogeneity within glioblastoma has focused attention on a subpopulation of cancer stem cells (CSCs) in glioblastoma, called brain tumor-initiating cells or glioblastoma stem-like cells (GSCs) [2], that are thought to contribute to tumor recurrence following therapy. Compared to their nonstem-cell counterparts (differentiated glioma cells, DGCs), GSCs exhibit resistance to chemotherapy- and radiation-induced cell death [3,4,5], often through cooption of signaling pathways relevant to normal stem cell physiology [6,7,8,9]. Our findings uncover an aberrant interaction between the Cox-2/PGE2 and Wnt pathways that mediates the stem-like state in glioblastoma
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