Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial in vivo intracranial transplantation

ABSTRACT: One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, the nature of the invasiveness remains poorly characterized. Here, we established a highly invasive glioma cell line (U87MGR2/R3 cells) and a non-invasive cell line (U87MGL2/L3 cells) from U87MG glioma cells following four rounds of serial in vivo intracranial transplantation. Compared to U87MGL2/L3 cells, U87MGR2/R3 cells were highly invasive and had glioma stem cell-like properties. Microarray analysis showed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated, whereas several cancer stem cell-relevant genes (Wnt10A, Frizzled 4, and CD44) were upregulated in U87MGR2/R3 cells compared to U87MGL2/L3 cells. U87MGR2/R3 cells were resistant to anticancer drug-induced cell death, which was partially due to downregulation of caspase3 and PDCD4. U87MGR2/R3 cells retained activated Wnt/β-catenin signaling through Frizzled 4, which was sufficient to control neurosphere formation. In addition, Frizzled 4 promoted expression of the epithelial to mesenchymal transition regulator, SNAI1, and acquisition of a mesenchymal phenotype. Taken together, our results indicate that Frizzled 4 may be a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and may be a major cause of GBM recurrence and poor prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21570 | GEO | 2010/04/29

SECONDARY ACCESSION(S): PRJNA127005

REPOSITORIES: GEO