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: 9.33). 03/2011; 71(8):3066-75. DOI: 10.1158/0008-5472.CAN-10-1495
Source: PubMed


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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    ABSTRACT: The invasiveness of glioblastoma is a major cause of poor prognosis and relapse. However, the molecular mechanism controlling glioma cell invasion is poorly understood. Here, we report that receptor activator of nuclear factor kappa-B (NFκB) ligand (RANKL) promotes glioma cell invasion in vivo, but not in vitro. Unlike the invasiveness under in vitro culture conditions, in vivo xenograft studies revealed that LN229 cells expressing high endogenous RANKL generated more invasive tumors than U87MG cells expressing relatively low endogenous RANKL. Consistently, RANKL-overexpressing U87MG resulted in invasive tumors, whereas RANKL-depleted LN229 generated rarely invasive tumors. We found that the number of activated astrocytes was markedly increased in the periphery of RANKL-high invasive tumors. RANKL activated astrocytes through NFκB signaling and these astrocytes in turn secreted various factors which regulate glioma cell invasion. Among them, transforming growth factor β (TGF-β) signaling was markedly increased in glioblastoma specimens and xenograft tumors expressing high levels of RANKL. These results indicate that RANKL contributes to glioma invasion by modulating the peripheral microenvironment of the tumor, and that targeting RANKL signaling has important implications for the prevention of highly invasive glioblastoma.
    Cancer Letters 07/2014; DOI:10.1016/j.canlet.2014.07.034 · 5.62 Impact Factor
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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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    ABSTRACT: Glioblastoma multiforme (GBM) is by far the most common and most aggressive malignant primary tumor in humans and has poor outcomes despite many advances in treatment using combinations of surgery, radiotherapy and chemotherapy. Recent studies demonstrate that GBM contains a subpopulation of cancer cells with stem cell characteristics, including self-renewal and multipotentiality, and that these cancer stem cells contribute to disease progression. MicroRNAs (miRNAs) are small non-coding regulatory RNA molecules that regulate a variety of cellular processes, including stem cell maintenance. An accumulating body of evidence shows that miR-218 may act as a tumor suppressor by inhibiting glioblastoma invasion, migration, proliferation and stemness through its different targets, indicating the great potential and relevance of miR-218 as a novel class of therapeutic target in glioblastoma.
    Cancer Letters 07/2014; 353(1). DOI:10.1016/j.canlet.2014.07.011 · 5.62 Impact Factor
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    • "The three major groups of transcription factors, the SNAI, TWIST, and Zinc-finger enhancer binding (ZEB) family members have been reported to be altered in GBM. Their overexpression follows the activation of WNT/β-catenin pathway and results in increased in vitro cell migration and invasion [23, 24]. It is likely that the high expression of mesenchymal genes in the mesenchymal subset of human GBMs [25] can be considered to be reminiscent of the EMT program [26] or that the aberrant activation of EMT factors during gliomagenesis can trigger the mesenchymal shift in GBM [27]. "
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    ABSTRACT: Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.
    04/2014; 2014:725921. DOI:10.1155/2014/725921
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