Potential use of glioblastoma tumorsphere: clinical credentialing

Kang, Seok‐Gu; Cheong, Jae‐Ho; Huh, Yong Min; Kim, Eui Hyun; Kim, Sun Ho; Chang, Jong Hee

doi:10.1007/s12272-015-0564-0

Cited by 24 publications

(29 citation statements)

References 40 publications

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“…27,28 In our study, rather than using specific GBM cell lines, we chose GBM-TS, as we believe new therapeutic approaches should target the subpopulation of GBM cells responsible for treatment failure. 29 Although the metabolic characteristics of TS have not been clearly elucidated, there are a number of reports that TS preferentially utilize glycolysis. 18,19 Other research based on the selective toxicity of metformin toward cancer stem cells (CSCs), however, supports a "reverse Warburg effect, " arguing that CSCs are more dependent on oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Because stem cells are known to be responsible for treatment resistance, metabolism-modulating interventions, with their inhibitory effects on stemness, could be a promising strategy for treating GBM patients. 29 Numerous reports have also suggested that tumor invasion is mediated by the CSC population. 34,35 Using a physiologically relevant in vivo-like tumor model, we investigated whether modulation of cancer metabolism could inhibit the invasive properties of GBM-TS by observing their 3D invasion into type I collagen-the most abundant matrix in the human body.…”

Section: Neurooncologymentioning

confidence: 99%

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Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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Background. Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods. Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemnessrelated proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness-and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

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Section: Discussionmentioning

confidence: 99%

Section: Neurooncologymentioning

confidence: 99%

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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“…It has been assumed that TSs arise from a subpopulation of cells responsible for the initiation, maintenance, and recurrence of tumors [2,18]. It is also commonly thought that TS-generating cells comprise some proportion of the tumor, and that a higher proportion of these TS-generating cells would be associated with a more aggressive tumor [3,15,19].…”

Section: Discussionmentioning

confidence: 99%

“…A subpopulation of glioblastoma (GBM) tumor cells possesses the ability to undergo neural differentiation and induce tumorigenesis [1][2][3]. When cultured under appropriate conditions in vitro, this population of tumor cells gives rise to gliomaspheres, referred to more generically as tumorspheres (TSs).…”

Section: Introductionmentioning

confidence: 99%

Success of tumorsphere isolation from WHO grade IV gliomas does not correlate with the weight of fresh tumor specimens: an immunohistochemical characterization of tumorsphere differentiation

et al. 2016

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BackgroundA trend of stage-by-stage increase in tumorsphere (TS) formation from glioma samples has been reported. Despite this trend, not all surgical specimens give rise to TSs, even World Health Organization (WHO) grade IV gliomas. Furthermore, it has been reported that differences in overall survival of primary glioblastoma patients depends on the propensity of their tumors to form TSs. However, the weights of fresh specimens vary from one surgical isolate to the next.MethodsAccordingly, we evaluated the relationship between the weights of surgical specimens in WHO grade IV gliomas with the capacity to isolate TSs. Thirty-five fresh WHO grade IV glioma specimens were separated into two groups, based on whether they were positive or negative for TS isolation, and the relationship between TS isolation and weight of surgical specimens was assessed.ResultsWe observed no significant difference in the weights of surgical samples in the two groups, and found that the optimal weight of specimens for TSs isolation was 500 mg.ConclusionThus, contrary to our expectations, the ability to isolate TSs from WHO grade IV glioma specimens was not related to the weight of fresh specimens.

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“…Therefore, vorinostat changes the expression of about 10% of disease‐related genes and may be effective in a broad range of solid tumors and haematological malignancies. Vorinostat has been reported to affect cells derived from several types of cancer, including head and neck squamous cell carcinoma, CTCL, hepatoma, multiple myeloma, and glioblastoma …”

Section: Discussionmentioning

confidence: 99%

Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells

Sung

Kim

Kwak

et al. 2019

Journal of Pineal Research

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Glioblastoma (GBM) is the most aggressive malignant glioma and most lethal form of human brain cancer (Clin J Oncol Nurs. 2016;20:S2). GBM is also one of the most expensive and difficult cancers to treat by the surgical resection, local radiotherapy, and temozolomide (TMZ) and still remains an incurable disease. Oncomine platform analysis and Gene Expression Profiling Interactive Analysis (GEPIA) show that the expression of transcription factor EB (TFEB) was significantly increased in GBMs and in GBM patients above stage IV. TFEB requires the oligomerization and localization to regulate transcription in the nucleus. Also, the expression and oligomerization of TFEB proteins contribute to the resistance of GBM cells to conventional chemotherapeutic agents such as TMZ. Thus, we investigated whether the combination of vorinostat and melatonin could overcome the effects of TFEB and induce apoptosis in GBM cells and glioma cancer stem cells (GSCs). The downregulation of TFEB and oligomerization by vorinostat and melatonin increased the expression of apoptosis‐related genes and activated the apoptotic cell death process. Significantly, the inhibition of TFEB expression dramatically decreased GSC tumor‐sphere formation and size. The inhibitory effect of co‐treatment resulted in decreased proliferation of GSCs and induced the expression of cleaved PARP and p‐γH2AX. Taken together, our results definitely demonstrate that TFEB expression contributes to enhanced resistance of GBMs to chemotherapy and that vorinostat‐ and melatonin‐activated apoptosis signaling in GBM cells by inhibiting TFEB expression and oligomerization, suggesting that co‐treatment of vorinostat and melatonin may be an effective therapeutic strategy for human brain cancers.

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Potential use of glioblastoma tumorsphere: clinical credentialing

Cited by 24 publications

References 40 publications

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Success of tumorsphere isolation from WHO grade IV gliomas does not correlate with the weight of fresh tumor specimens: an immunohistochemical characterization of tumorsphere differentiation

Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells

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