Research Article
Wnt activation is implicated in glioblastoma radioresistance

https://doi.org/10.1038/labinvest.2011.161Get rights and content
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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 β-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+/Sox2+ population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.

Keywords

glioblastoma
radioresistance
stem cell
Wnt

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Supplementary Information accompanies the paper on the Laboratory Investigation website

Yonghyun Kim and Kang Ho Kim: These authors contributed equally to this work.

The Wnt signaling pathway is up-regulated in radiation-enriched glioblas toma stem cell-like cells, which makes them radioresistant; inhibition of Wnt signaling sensitizes the cells to radiation. Thus, targeting Wnt may assist radiation therapy in glioblastoma patients.

Supplementary information: The online version of this article (doi:10.1038/labinvest.2011.161) contains supplementary material, which is available to authorized users.