Medulloblastoma: novel insights into emerging therapeutic targets

Abstract

The tumor microenvironment, which includes the vasculature, is critical to tumor progression. The vasculature architecture can also influence therapeutic response by modulating the delivery of chemotherapy. Only a few studies have looked at vascular biology in medulloblastoma tumors, although existing studies suggest that neurodevelopmental pathways and chromatin-remodelers may contribute to angiogenic growth in these tumors. Clinical studies with bevacizumab in combination with radiation or chemotherapy have not been very successful. Chromatin remodelers can be pharmacologically targeted, and should be evaluated in pre-clinical models for their anti-angiogenic activity.

Keywords: Medulloblastoma; REST; VEGF; angiogenesis; tumor-microenvironment; vasculature.

Figure 1.

Schematic representation of angiogenic pathways in WNT, SHH and Group 3 medulloblastomas. (A) WNT ligand binding to FRIZZLED (Frz) receptor activates downstream signaling and β-Catenin activation, which is known to increase the expression of VEGF either directly [30], or through activation of NOTCH signaling [28]. β-Catenin can also induce IL8 and VEGF expression [30]. (B) In SHH medulloblastoma, loss of the tumor suppressor PTCH1 promotes oncogenic Smoothened (SMO) activity and downstream signaling through Glioma associated oncogene (GLI)-1 transcription factor. Gli1 can upregulate HIF1-α and AKT and activate pro-angiogenic CXCR4 signaling. HIF1-α can also directly upregulate the expression of other pro-angiogenic molecules such as VEGF, FLT1, FLK1, ANG1, ANG2 and FGF. REST elevation in SHH medulloblastoma cells has been shown to elevate AKT, FLT1 and VEGF levels [38, 39]. (C) In Group 3 medulloblastoma, MYC elevation in response to an unknown extracellular signal (?) can upregulate VEGFA expression to promote vascular growth [47].