Targeting WNT Signaling for Multifaceted Glioblastoma Therapy

Abstract

The WNT signaling pathway has been of great interest to developmental biologists for decades and has more recently become a central topic for study in cancer biology. It is vital for cell growth and regulation of embryogenesis in many organ systems, particularly the CNS and its associated vasculature. We summarize the role of WNT in CNS development and describe how WNT signaling makes key contributions to malignant glioma stemness, invasiveness, therapeutic resistance, and angiogenesis. The role of WNT in these mechanisms, along with creation and maintainance of the blood-brain barrier (BBB), points to the potential of WNT as a multi-faceted target in malignant glioma therapy.

Keywords: WNT; angiogenesis; cancer biology; drug delivery; glioblastoma.

Figure 1

Overview of WNT signaling pathway activation. (Left) WNT signaling inactivation with absence of the WNT ligand. Phosphorylation of β-catenin resulted in Dishevelled (DVL), Axin, APC and GSK3β complex resulting in proteosomal degradation. (Right) Canonical WNT signaling activation after WNT ligand binding. Unphosphorylated β-catenin enters the nucleus to drive transcription affecting such genes as C-MYC, SOX9, CD44.

Figure 2

Potential benefits of inhibiting WNT signaling. (A) WNT inhibition blocking innate features of tumor biology could decrease tumor cell stemness, prevent tumor invasiveness and decrease therapeutic resistance. (B) Inhibition impacts glioblastoma vasculature by blocking angiogenesis. (C) Signaling inhibition results in increased BBB permeability allowing for improved chemotherapy delivery.