Frizzled 4 Regulates Stemness and Invasiveness of Migrating Glioma Cells Established by Serial Intracranial Transplantation

School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Cancer Research (Impact Factor: 9.28). 03/2011; 71(8):3066-75. DOI: 10.1158/0008-5472.CAN-10-1495
Source: PubMed

ABSTRACT One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, which is 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, its nature remains poorly understood. In this study, we established highly serial intracranial transplantation. U87R4 cells were highly invasive and displayed stem cell-like properties, as compared to noninvasive but proliferative U87L4 cells. Microarray analysis during serial transplantation revealed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated whereas several cancer stem cell-relevant genes [Frizzled 4 (FZD4) and CD44] were upregulated in more invasive cells. U87R4 cells were resistant to anticancer drug-induced cell death, partly due to downregulation of caspase3 and PDCD4, and they retained activated Wnt/β-catenin signaling due to upregulation of Frizzled 4, which was sufficient to control neurosphere formation. We also found that FZD4 promoted expression of the epithelial to mesenchymal transition regulator SNAI1, along with acquisition of a mesenchymal phenotype. Taken together, our results argue that Frizzled 4 is a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and that it may be a major cause of GBM recurrence and poor prognosis.

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    • "The invasiveness of glioma cells is the main cause of poor prognosis and resistance to current therapeutic intervention [2]. Our previous study revealed that receptor activator of nuclear factor kappa-B ligand (RANKL) expression is significantly increased in invasive glioma cell lines [3]. RANKL is a member of the tumor necrosis factor family and acts as a ligand for RANK. "
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    • "These findings suggest that miR-218 regulates the glioblastoma stemness through a Bmi1-mediated epigenetic pathway. FZD4 and LEF1, which are involved in the Wnt pathway, are regulated by miR-218 and also affect glioblastoma stem cell stemness [93]. However, there are few reports on miR-218 and glioblastoma stem cell stemness; thus, it is necessary to further clarify the mechanism through which miR-218 regulates glioblastoma stemness. "
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    • "These changes are related both to the alternating proliferative and quiescent cancer stem cell phenotypes (Fig. 1) and to the topological network phase transitions mentioned before. Importantly , the quiescent cancer stem cell phenotype often coincides with the invasive phenotype [98] [99] [100]. It is rather plausible that high mobility and invasiveness requires a more rigid network structure up to the level of cytoskeletal networks, since physical force required for both migration and invasion can only be exercised efficiently , if the underlying network is not plastic (Fig. 1). "
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