Activation of the Wnt/β-Catenin signaling pathway in glioma stem cells impacts blood-brain barrier integrity

Authors

• A Vezina
• MR Gilbert
• S Jackson

Abstract

Glioma stem cells (GSC) are involved in glioblastoma (GBM) resistance to therapy and recurrence. GBM treatment is impacted by poor drug delivery across the low permeable and highly selective blood-brain barrier (BBB). Moreover, increased Wnt/β-catenin signaling in GBM is associated with radioresistance and proliferation. Interestingly, activating mutations of β-catenin in Wnt-subtype medulloblastoma is associated with good prognosis and a highly permeable BBB. We propose that activation of WNT/β-catenin signaling in GSCs will decrease brain endothelial cell junctional integrity to increase BBB permeability. We used CHIR99021, a glycogen synthase kinase 3β inhibitor, to activate Wnt/β-catenin signaling in the GSC line, GSC923. Human brain microvascular endothelial cells (HBMEC) were treated with conditioned media from GSC923 treated with or without CHIR99021. Endothelial barrier function was evaluated by electrical cell impedance and recorded using the ACEA xCELLigence system. HBMEC cell index was decreased by 60% when treated with conditioned medium from Wnt/β-catenin activated GSC923 cells; suggesting decreased cell-cell interactions and increased permeability. Additionally, endothelial junctional proteins, claudin-1, -3, -5, Occludin, ZO-1, and VE-cadherin, gene expression was decreased. Further characterization of secreted proteins by GSC923, assessed by mass spectrometry, is ongoing to evaluate which specific Wnt/β-catenin downstream proteins impact the BBB. Our findings suggest that disruption of brain endothelial junctional interactions occurs in a paracrine manner, under the Wnt/β-catenin signaling axis from glioma stem cells to HBMEC. Modulation of intratumoral Wnt/β-catenin signaling, particularly on highly resistant GSCs, may serve an important clinical application tool to enhance chemotherapy drug delivery and potentially improve GBM disease prognosis.

Scientific Focus Area: Cancer Biology

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