Wnt activation is implicated in glioblastoma radioresistance

Abstract

Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active b-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC þ /Sox2 þ population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.

Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in Glioma Stem Cells

“…The Notch signaling pathway is known to be important for the maintenance of stemness and radioresistance of GSCs [31,37]. In addition, activation of Wnt/b-catenin signaling confers tumorigenesis, invasiveness, and radioresistance on GSCs [38], and STAT3 signaling regulates the Notch pathway and is crucial for the stemness and tumorigenicity of GSCs [39]. Together, our data strongly suggest that emodin acts as a potent suppressor of stemness in GSCs.…”

Cancer stem cells: emerging actors in both basic and clinical cancer research

“…The Wnt pathway also contributes to the malignant transformation of stem/ progenitor cells (Reya and Clevers, 2005). In addition, it has been showed that the Wnt pathway contributes to radioresistance in glioblastoma multiforme and head and neck CSCs (Chang et al, 2008;Kim et al, 2012).…”

Glioma cancer stem cells and their role in therapy

“…It was shown that treatment with ionizing radiation enriched the glioblastoma cell population with GCSCs positive for activated stem cell-associated pathways such as β-catenin (ABC), Sox2 and Wnt. (Kim et al, 2012). The molecular mechanism of radiation resistance of GBM is mediated by selection of subpopulation of GCSCs with activated stem cells genes in addition; radioresistance of GBM is not simply an intrinsic characteristic of glioma stem cells but a result of interactions between these cells and microenvironmental factors (Mannino and Chalmers, 2011).…”