Frizzled 4 Regulates Stemness and Invasiveness of Migrating Glioma Cells Established by Serial Intracranial Transplantation
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.
- SourceAvailable from: Ichiro Nakano
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- "The invasiveness of glioma cells is the main cause of poor prognosis and resistance to current therapeutic intervention . Our previous study revealed that receptor activator of nuclear factor kappa-B ligand (RANKL) expression is significantly increased in invasive glioma cell lines . RANKL is a member of the tumor necrosis factor family and acts as a ligand for RANK. "
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 . 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. "
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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- "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   . 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). "
ABSTRACT: Cancer is increasingly perceived as a systems-level, network phenomenon. The major trend of malignant transformation can be described as a two-phase process, where an initial increase of network plasticity is followed by a decrease of plasticity at late stages of tumor development. The fluctuating intensity of stress factors, like hypoxia, inflammation and the either cooperative or hostile interactions of tumor inter-cellular networks, all increase the adaptation potential of cancer cells. This may lead to the bypass of cellular senescence, and to the development of cancer stem cells. We propose that the central tenet of cancer stem cell definition lies exactly in the indefinability of cancer stem cells. Actual properties of cancer stem cells depend on the individual "stress-history" of the given tumor. Cancer stem cells are characterized by an extremely large evolvability (i.e. a capacity to generate heritable phenotypic variation), which corresponds well with the defining hallmarks of cancer stem cells: the possession of the capacity to self-renew and to repeatedly re-build the heterogeneous lineages of cancer cells that comprise a tumor in new environments. Cancer stem cells represent a cell population, which is adapted to adapt. We argue that the high evolvability of cancer stem cells is helped by their repeated transitions between plastic (proliferative, symmetrically dividing) and rigid (quiescent, asymmetrically dividing, often more invasive) phenotypes having plastic and rigid networks. Thus, cancer stem cells reverse and replay cancer development multiple times. We describe network models potentially explaining cancer stem cell-like behavior. Finally, we propose novel strategies including combination therapies and multi-target drugs to overcome the Nietzschean dilemma of cancer stem cell targeting: "what does not kill me makes me stronger".Seminars in Cancer Biology 01/2014; DOI:10.1016/j.semcancer.2013.12.004 · 9.33 Impact Factor