The role of Src family kinases in growth and migration of glioma stem cells

Han, Xiaosi; Zhang, Wenbin; Yang, Xiuhua; Wheeler, Crystal G.; Langford, Catherine P.; Wu, Lu; Filippova, Natalia; Friedman, Gregory K.; Ding, Qiang; Fathallah‐Shaykh, Hassan M.; Gillespie, G. Yancey; Nabors, L. Burt

doi:10.3892/ijo.2014.2432

Cited by 50 publications

(44 citation statements)

References 40 publications

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“…Chromatin immunoprecipitation revealed ZBTB18 binding at ACTN1 , PTRF , SERPINE1 and CD97 promoters (Figure 2B), indicating that, at least for a subset of targets, ZBTB18 is directly involved in gene repression. To better understand the role of ZBTB18 in high grade gliomas, we performed overexpression studies and subsequent gene set enrichment analysis (GSEA http://software.broadinstitute.org/gsea/index.jsp) on mesenchymal patient-derived brain tumor stem cell like cell line (BTSC233, Figure 1D-E and Figure 2C-D) and a patient-derived GBM xenoline (JX6) [24] which was classified as classical according to the Verhaak study (Figure 1D-E and Figure 2E-F). Interestingly, we also detected a lower band similar to those observed in GBM-derived cells at around 30 kDa (Figure 2C, E and Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Fedele

Dai

Masilamani

et al. 2017

Molecular Cancer Research

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Glioblastoma (GBM) is comprised of distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass.

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Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Fedele

Dai

Masilamani

et al. 2017

Molecular Cancer Research

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“…Collected cells were washed twice with serumless DMEM/F12 (300×G, 7 minutes, 4°C), counted in the presence of 0.04% trypan blue to enumerate viable cells. Dissociated LGG cells were cultured in cell culture plates coated with poly-L-ornithine (Sigma-Aldrich) and laminin (EMD-Millipore) in LGG medium (Neurobasal-A medium containing 1% N-2, 2% vitamin A-free B-27, 2 mM L-Glutamine [Thermo Fisher], 20 ng/ml basic FGF [Stemgent], and 20 ng/ml human EGF [Cell Signaling]) as described [15,16]. Medium was exchanged as needed, and cells grew adherently to the bottom of flasks.…”

Section: Methodsmentioning

confidence: 99%

Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis

et al. 2018

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Introduction. IDH1 mutation has been identified as a early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. Methods. We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). Results. We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPCS clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. Conclusions. These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.

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“…It was shown to inhibit ligand-induced EphA2 internalization and subsequent degradation in pancreatic cell lines (132). Of interest, dasatinib inhibited the Src family of kinases, involved in the Eph downstream signalling, significantly suppressing proliferation of primary glioma cells, but it had no measurable inhibitory effect on the growth of glioma stem-like cells (133). The results of a phase I clinical trial of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, during and after radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG), were recently published.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Ephs and Ephrins in malignant gliomas

Ferluga

Debinski

2014

Growth Factors

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Eph receptor tyrosine kinases and the corresponding ephrin ligands play a pivotal role in glioma development and progression. Aberrant protein expression levels of the Eph receptors and ephrins are often associated with higher tumor grade and poor prognosis. Their function in tumorigenesis is complex due to the intricate network of possible co-occurring interactions between neighboring tumor cells and tumor microenvironment. Both Ephs and ephrins localize on the surface of tumor cells, tumor vasculature, glioma stem cells tumor cells infiltrating brain and immune cells infiltrating tumors. They can both promote and inhibit tumorigenicity depending on the downstream forward and reverse signalling generated. All the above-mentioned features make the Ephs/ephrins system an intriguing candidate for the development of new therapeutic strategies in glioma treatment. This review will give a general overview on structure and function of Ephs and ephrins, with particular emphasis on the state-of-the-knowledge of their role in malignant gliomas.

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The role of Src family kinases in growth and migration of glioma stem cells

Cited by 50 publications

References 40 publications

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis

Ephs and Ephrins in malignant gliomas

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