Primary glioblastoma cultures: can profiling of stem cell markers predict radiotherapy sensitivity?

Lemke, Dieter; Weiler, Markus; Blaes, Jonas; Wiestler, Benedikt; Jestaedt, Leonie; Klein, Ann Catherine; Low, Seng Hui; Eisele, Günter; Radlwimmer, Bernhard; Capper, David; Schmieder, Kirsten; Mittelbronn, Michel; Combs, Stephanie E.; Bendszus, Martin; Weller, Michael; Platten, Michael; Wick, Wolfgang

doi:10.1111/jnc.12802

Cited by 48 publications

(51 citation statements)

References 50 publications

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“…To further explore the mechanisms of tunicamycin reducing GICs self-renewal, we investigated whether tunicamycin reduced the expression of genes regulating the self-renewal of glioma-initiating cell [24, 25]. Western blot assay and immunofluorescence assay showed that tunicamycin obviously reduced the expression of Sox2 (Figure 4A and 4B), a key gene sustaining self-renewal of normal and cancer stem cell [26–28].…”

Section: Resultsmentioning

confidence: 99%

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation

Yang

Liu

et al. 2016

Oncotarget

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Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma-initiating cell to initiate tumor formation. Although tunicamycin induces glioma-initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells.

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Section: Resultsmentioning

confidence: 99%

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation

Yang

Liu

et al. 2016

Oncotarget

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“…Although triple treatment did not further reduce CD133 + surface population compared to dual treatments, it reduced SOX2 expression a widely used marker for repopulating cells in context of radiation resistance [41–42] as well as Nestin another stem cell marker in glioma progression [43–44]. This suggests that the treatment resistant population sensitive to NOTCH inhibitors is contained within the CD133, SOX2 and Nestin overlap expression.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the treatment resistant population sensitive to NOTCH inhibitors is contained within the CD133, SOX2 and Nestin overlap expression. The phenotypic and functional identity of this population in vivo would be a key step forward in understanding glioma treatment resistance [45]. …”

Section: Discussionmentioning

confidence: 99%

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

et al. 2016

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Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

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“…20,21 CD44 protein marker expression correlates with molecular subtype of GBM 22 and positively associated with radioresistance of glioblastoma. 23 Data on the prognostic significance of CD44 in glioblastoma are controversial -it was suggested that enhanced CD44 expression is associated with poor survival rates in glioblastoma although this finding was not statistically significant; 24 lower levels of CD44 expression surprisingly correlated with lower survival for GBM patients. 25 Ki-67 is an established marker of cell proliferation, and Ki-67 index correlates with the clinical course of several cancer types.…”

Section: Introductionmentioning

confidence: 99%

Prognostic relevance of NG2/CSPG4, CD44 and Ki-67 in patients with glioblastoma

et al. 2017

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Neuron-glial antigen 2 (NG2, also known as CSPG4) and hyaluronic acid receptor CD44 are chondroitin sulphate proteoglycans actively involved in brain development and its malignant transformation. Here, we aimed to compare prognostic significances of NG2, CD44 and Ki-67 expression in glioblastoma multiforme patients. Totally, 45 tissue samples and 83 paraffin-embedded tissues for 75 patients were analysed. The prognostic values of the genes were analysed using Kaplan-Meier survival curves. Grade III gliomas showed 2-fold difference in NG2 expression between anaplastic astrocytoma and oligoastrocytoma (10.1 ± 3.5 and 25.5 ± 14.5, respectively). For grade IV gliomas, upregulated NG2 expression (21.0 ± 6.8) was associated with poor glioblastoma multiforme prognosis (overall survival < 12 months) compared with glioblastoma multiforme patients with good prognosis (4.4 ± 3.2; overall survival > 12 months). Multivariate survival analysis using Cox proportional hazards model confirmed that high NG2 expression was associated with low survival of the patients (hazard ratio: 3.43; 95% confidence interval: 1.18-9.93; p = 0.02), whereas age (hazard ratio: 1.02; 95% confidence interval: 0.96-1.09; p = 0.42), tumour resection (hazard ratio: 1.03; 95% confidence interval: 0.98-1.08; p = 0.25) and sex (hazard ratio: 0.62; 95% confidence interval: 0.21-1.86; p = 0.40) did not show significant association with prognosis. Although the positive correlation was shown for NG2 and CD44 expression in the glioblastomas (Pearson coefficient = 0.954), Kaplan-Meier and multivariate survival analyses did not revealed a significant association of the increased CD44 expression (hazard ratio: 2.18; 95% confidence interval: 0.50-9.43; p = 0.30) or high Ki-67 proliferation index (hazard ratio: 1.10; 95% confidence interval: 1.02-1.20; p = 0.02) with the disease prognosis. The results suggest that upregulation of NG2/CSPG4 rather than changes in CD44 or Ki-67 expression is associated with low overall survival in glioblastoma multiforme patients, supporting NG2/CSPG4 as a potential prognostic marker in glioblastoma.

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Primary glioblastoma cultures: can profiling of stem cell markers predict radiotherapy sensitivity?

Cited by 48 publications

References 50 publications

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

Prognostic relevance of NG2/CSPG4, CD44 and Ki-67 in patients with glioblastoma

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