Neuronal Transcription Factors Induce Conversion of Human Glioma Cells to Neurons and Inhibit Tumorigenesis

Zhao, Junli; He, Hua; Zhou, Kesong; Ren, Yongcheng; Shi, Zheng; Wu, Zhiyuan; Wang, Yizheng; Lu, Yao; Jiao, Jianwei

doi:10.1371/journal.pone.0041506

Cited by 39 publications

(45 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that transient expression of Ngn2 (by a non-donor episomal plasmid) in radial glia was sufficient to produce ATRT like tumors. The effectiveness of transient Ngn2 expression, in combination with previous findings that Ngn2 or NeuroD1 expressed in glioma cells induces cell death and neuronal differentiation without changing tumor type (46, 47) supports the idea that Ngn2 and NeuroD1 acts in early stage radial progenitors to change the type of tumor generated. We have co-expressed Ngn2 with GFAP donor plasmids and found the resulted tumors were similar to tumors induced by GFAP donor plasmids alone.…”

Section: Discussionsupporting

confidence: 79%

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

Chen

Becker

LoTurco

2014

Molecular Cancer Research

View full text Add to dashboard Cite

The etiology of central nervous system (CNS) tumor heterogeneity is unclear. To clarify this issue, a novel animal model was developed of glioma and atypical teratoid/rhabdoid-like tumor (ATRT) produced in rats by non-viral cellular transgenesis initiated in utero. This model system affords the opportunity for directed oncogene expression, clonal labeling, and addition of tumor-modifying transgenes. By directing HRasV12 and AKT transgene expression in different cell populations with promoters that are active ubiquitously (CAG promoter), astrocyte-selective (GFAP promoter), or oligodendrocyte-selective (MBP promoter); thus, generating glioblastoma multiforme (GBM) and anaplastic oligoastrocytoma (AO), respectively. Importantly, the GBM and AO tumors were distinguishable at both the cellular and molecular level. Furthermore, proneural basic-helix-loop-helix (bHLH) transcription factors, Ngn2 (NEUROG2) or NeuroD1, were expressed along with HRasV12 and AKT in neocortical radial glia, leading to the formation of highly lethal atypical teratoid/rhabdoid-like tumors (ATRT). This study establishes a unique model in which determinants of CNS tumor diversity can be parsed out and reveals that both mutation and expression of neurogenic bHLH transcription factors contributes to CNS tumor diversity.

show abstract

Section: Discussionsupporting

confidence: 79%

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

Chen

Becker

LoTurco

2014

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…The prognosis of patients with glioma remains poor despite improved treatment modalities, including maximum surgical resection, chemotherapy with anti-neoplastic drugs and radiotherapy 2,3 . Temozolomide (TMZ), an alkylating agent, has shown promising results in the treatment of newly diagnosed patients with glioblastoma multiforme or refractory anaplastic astrocytoma when used as single agent as well as in combination with radiation therapy 4 .…”

Section: Introductionmentioning

confidence: 99%

“…The tumors still grew after 30 days, and tumors from Si-MEK2-infected cells were smaller than those from Si-ctl-infected cells. The mean tumor burden of Si-ctl-infected cells was 125.75 6 114 mm3 (n 5 8) and of Si-MEK2-infected cells was 10.32 6 2.65 mm 3 (n 5 8, P 5 0.013 vs. Si-ctl) (Figure 6e). The function of MEK2 in glioma cell growth.…”

mentioning

confidence: 96%

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Yao

Zhang

et al. 2015

Cell Mol Immunol

Self Cite

View full text Add to dashboard Cite

Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

show abstract

“…Registration of the two locations within the glioma with predetermined Cho/Cr ratios was carried out as previously described 20. Tumor samples were obtained by experienced neurosurgeons following standard procedures 21. Specimens from each location were divided and immediately sent for neurosphere culture and histopathological evaluation.…”

Section: Methodsmentioning

confidence: 99%

Multivoxel magnetic resonance spectroscopy identifies enriched foci of cancer stem-like cells in high-grade gliomas

Qiu

Wang

et al. 2017

OTT

View full text Add to dashboard Cite

ObjectiveThis study investigated the correlation between choline/creatine (Cho/Cr) ratios determined by multivoxel proton magnetic resonance spectroscopy (1H-MRS) and the distribution of cancer stem-like cells (CSLCs) in high-grade gliomas.Patients and methodsSixteen patients with high-grade gliomas were recruited and underwent 1H-MRS examination before surgery to identify distinct tumor regions with variable Cho/Cr ratios. Using intraoperative neuronavigation, tumor tissues were accurately sampled from regions with high and low Cho/Cr ratios within each tumor. The distribution of CSLCs in samples from glioma tissue regions with different Cho/Cr ratios was quantified by neurosphere culture, immunohistochemistry, and Western blot.ResultsThe mean neurosphere formation rate in tissues with high Cho/Cr ratios was significantly increased compared with that in low Cho/Cr ratio tissues (13.94±5.94 per 100 cells vs 8.04±3.99 per 100 cells, P<0.001). Immunohistochemistry indicated that tissues with high Cho/Cr ratios had elevated expression of CD133, nestin, and CD15, relative to low Cho/Cr ratio tissue samples (23.6%±3.8% vs 18.3%±3.3%, 25.2%±4.5% vs 19.8%±2.8%, 24.5%±3.8% vs 17.8%±2.2%, respectively; all P<0.001). Western blot demonstrated that relative CD133 and nestin protein expression in high Cho/Cr ratio regions was significantly higher than that in low Cho/Cr ratio tissue samples (0.50±0.17 vs 0.30±0.08, 0.45±0.13 vs 0.27±0.07, respectively; both P<0.001). The protein expression levels of CD133 and nestin were highly correlated with Cho/Cr ratios (r=0.897 and r=0.861, respectively).ConclusionCho/Cr ratios correlate with the distribution of CSLCs in high-grade gliomas, and this may assist in identifying foci enriched with CSLCs and thus improve the management of high-grade gliomas.

show abstract

Neuronal Transcription Factors Induce Conversion of Human Glioma Cells to Neurons and Inhibit Tumorigenesis

Cited by 39 publications

References 29 publications

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Multivoxel magnetic resonance spectroscopy identifies enriched foci of cancer stem-like cells in high-grade gliomas

Contact Info

Product

Resources

About