Major finding: WNT medulloblastoma is the only medulloblastoma subtype that lacks an intact BBB.
Mechanism: WNT medulloblastomas secrete WNT antagonists that block normal endothelial WNT signaling.
Impact: WNT antagonists may increase BBB permeability and enhance drug response in medulloblastomas.
Medulloblastomas (MB), which are highly malignant pediatric brain tumors, consist of four molecular subtypes: WNT, SHH, group 3 MB, and group 4 MB, the latter three of which are most likely to exhibit a poor clinical outcome. In contrast, patients with WNT MBs who are given the standard-of-care treatment exhibit a significantly high overall 5-year survival rate. To identify the factors driving MB subtype–specific treatment response, Phoenix and colleagues examined two patient cohorts and transgenic murine models of WNT MB, SHH MB, and group 3 MB. Analysis of these patient cohorts and mouse models revealed that WNT MBs were more hemorrhagic and exhibited significantly higher vascular density and aberrant vascular endothelium than the other MB subtypes. Consistent with these findings, WNT MB endothelium exhibited downregulation of genes associated with central nervous system endothelium and the blood–brain barrier (BBB) as well as with NOTCH signaling, and WNT MBs were found to lack a functional BBB in vivo. Mechanistically, the secretion of WNT antagonists, such as dickkopf WNT pathway signaling inhibitor 1 (DKK1) and WNT inhibitor factor 1 (WIF1), by WNT MBs blocked WNT signaling in adjacent normal endothelium. Expression of the WNT7A ligand in WNT MB restored canonical WNT signaling in tumor endothelium and a functional BBB in vivo, and expression of WIF1-DKK1 in SHH MB suppressed WNT signaling and increased vessel porosity. Vincristine treatment was efficacious against control WNT MB and ineffective against WNT7A-secreting WNT MB in vivo. Together, these results identify the molecular mechanism underlying the responsiveness of WNT MB to therapy and suggest a potential therapeutic strategy to increase drug penetrance of the BBB.
- ©2016 American Association for Cancer Research.
Volume 6, Issue 6
