Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

Yoon, Seon‐Jin; Park, Junseong; Jang, Dong Su; Kim, Hyun Jung; Lee, Joo Ho; Jo, Euna; Choi, Ran Joo; Shim, Jin Kyung; Moon, Ju Hyung; Kim, Eui Hyun; Chang, Jong Hee; Lee, Jehee; Kang, Seok‐Gu

doi:10.3340/jkns.2019.0129

Cited by 22 publications

(31 citation statements)

References 72 publications

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“…In the case of GBM, the cell of origin is in the subventricular zone (Yoon et al 2020 ; Lee et al 2018 ), but the cells in which the tumor is present are a realistic therapeutic target. Cancer stem cells (CSCs) have been tested as targets of therapeutic agents because such cells are resistant to chemotherapy (Dean et al 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

Shim

Park

et al. 2020

J Cancer Res Clin Oncol

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Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. Methods GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Results Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. Conclusion The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

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Section: Discussionmentioning

confidence: 99%

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

Shim

Park

et al. 2020

J Cancer Res Clin Oncol

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“…Thus, adjuvant therapy targeting resident cancer cells is crucial for reversing poor survival rates. A significant subpopulation of GBM cancer cells that can survive conventional chemotherapy is proposed to possess stem cell-like features and heterogeneity [ 3 , 4 , 5 , 6 , 7 , 8 ]. Therapeutic tolerance and relapse of surviving cancer cells is fueled by glycolysis and oxidative phosphorylation, known to serve as major suppliers of ATP for cancer cells [ 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Surgery is the most effective treatment for complete resection, but unlike tumors of other organs, it is impossible to remove whole brain with tumors. Resident cancer cells with stem cell-like features and heterogeneity induce therapeutic tolerance and relapse, facilitating glioblastoma (GBM) survival and proliferation characterized by GBM tumorspheres (TSs) [ 3 , 4 , 5 , 6 , 7 ]. In view of the limitations of surgery alone, temozolomide (TMZ), an alkylating agent, in conjunction with postoperative radiation is employed as the standard of care for GBM.…”

Section: Introductionmentioning

confidence: 99%

“…However, TMZ is insufficient for complete elimination of resistant GBM TSs. For these reasons, targeting the universal features of cancer cells is an emerging therapeutic strategy to overcome resistance to conventional cancer therapy and tumor recurrence [ 5 , 6 , 7 , 8 ]. Modulation of cancer cell metabolism through depletion of glucose and oxidative phosphorylation, the main source of tumor energy, is one such novel approach [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres

Park

Cho

et al. 2021

Molecules

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Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.

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“…TP53 mutation is one of the most common alterations across tumor types [ 22 ], and is observed in the early stages of GBM, along with changes in related pathways [ 17 , 67 , 68 ]. However, its association with GBM TS isolation rate was not reported yet [ 1 , 41 , 44 , 47 , 69 – 71 ].…”

Section: Discussionmentioning

confidence: 99%

Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres

et al. 2020

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Background Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. Conclusions GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

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Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

Cited by 22 publications

References 72 publications

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres

Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres

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