Rogue one: another faction of the Wnt empire implicated in assisting GBM progression

Abstract

It remains incumbent on researchers to conceive novel treatments for the most common primary malignancy of the brain in adults, glioblastoma multiforme (GBM), as the standard of care for patients today fails to yield a median survival beyond two years following diagnosis. Recent studies have tended towards appreciating the cellular heterogeneity of GBM tumors, focusing on the subpopulation of highly plastic glioblastoma stem cells (GSCs). In the November 2016 issue of Cell, Hu and colleagues developed a de nova GBM model derived from immortalized neural stem cells and, using this model, they demonstrated that GSCs can generate CD133⁺/CD144⁺ cells with endothelial cell-like characteristics. Contrasts between the epigenetic state and gene expression level before and after oncogenic transformation of this utilized de novo model for GBM implicated WNT5A, which has been previously shown to play a role in endothelial cell proliferation and migration via non-canonical Wnt signaling, as a mediator of the process. The transdifferentiation was accompanied by alterations in the histone marks at the gene loci of WNT5A, and its transcription factors PAX6 and DXL5. The authors hypothesize that activation of AKT, an aberration of the RTK/PTEN/PI3K pathway observed in the majority of GBM cases, triggers these epigenetic changes causing WNT5A expression. This phenomenon is of obvious clinical significance, as it provides an insight into how GBM may circumvent therapies targeting angiogenesis to achieve the neovascularization required to sustain invasive growth. The unveiling of this atypical differentiation process also raises questions about its interaction with the radiotherapy and chemotherapy commonly used to counter GBM progression. Here, we review the recent efforts to understand the complex mechanisms behind the plasticity of GSCs.

Keywords: GCS-derived endothelial-like cells; Glioblastoma; WNT5A; cellular plasticity; glioma stem cell (GSC); vascular mimicry.

Figure 1

The activation of AKT stimulates a switch in histone modifications at the locus of the Wnt5a gene from repressive H3K27 trimethylation to activating H3K27 acetylation. This is mirrored at the gene locus of its transcriptional activator DLX5. Contrastingly, the histones at the promoter of Pax6, a transcription factor that downregulates Wnt5a, gained repressive H3K27me3 marks. These epigenetic alterations have the net effect of increasing Wnt5a expression in induced glioma stem cells compared to their parental human neural stem/progenitor cells.

Figure 2

Glioblastoma stem cells are characterized by self-renewal, the potential for specialization to multiple lineages and aberrant transdifferentiation. Wnt5A expression most likely activates the Wnt/Ca²⁺ pathway via autocrine signalling, leading to their differentiation into endothelial-like cells. The lineage reprograming capacity of these cells remains a mystery. Will they respond to drugs targeting their endothelial-like phenotypes by going back to an undifferentiated state or switching their lineage? To what extent are the hallmarks of cancer stem cells preserved in these endothelial-like cells?