Dedifferentiation of patient‐derived glioblastoma multiforme cell lines results in a cancer stem cell‐like state with mitogen‐independent growth

Olmez, Inan; Shen, Wangzhen; McDonald, Hayes; Özpolat, Bülent

doi:10.1111/jcmm.12479

Cited by 54 publications

(59 citation statements)

References 44 publications

(63 reference statements)

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“…1B). Since neurosphere formation in vitro is correlated with tumor-forming potential of GICs (17), we tested with a self-renewal assay and observed that the combined treatment suppressed sphere formation significantly (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblotting was performed as previously described (17). The following antibodies were used for immunoblotting: Bcl-2 (sc-7382), Cyclin A (sc-751), CDK4 (sc-260), CDK6 (sc-177), and mTOR (sc-1549) antibodies were from Santa Cruz, Actin (A5441) and GAPDH (G9545) were from Sigma-Aldrich, and all other antibodies including Cyclin D1 (2978), PARP (9542), phospho-mTOR Ser2448 (2971), phospho-p70 S6K Thr389 (9234), phospho-S6 Ser235/236 (4858), p70 S6K (2708), S6 (2317), phospho-p44/42 Erk1/2 Thr202/Tyr204 (9101), and p44/42 Erk1/2 (9102) as well as antibody array kit (7949) were from Cell Signaling.…”

Section: Methodsmentioning

confidence: 99%

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Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez

Brenneman

Xiao

et al. 2017

Clinical Cancer Research

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Purpose Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez

Brenneman

Xiao

et al. 2017

Clinical Cancer Research

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“…Olmez et al 38 recently demonstrated the difficulty of dealing with CSCs by inducing dedifferentiation of patient-derived GBM cell lines into GSC-like cells (induced GBM stem cells, iGSCs) through the expression of Oct4, Sox2, and Nanog transcription factors. The iGSCs formed neurospheres even in the absence of exogenous mitogens, were sensitive to the CSC inhibitor salinomycin, and exhibited resistance to temozolomide (TMZ) therapy.…”

Section: Cancer Stem Cells and Apoptosismentioning

confidence: 99%

Resistance to Cell Death and Its Modulation in Cancer Stem Cells

2016

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Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs. Several signaling pathways—including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin—and expression of the CSC markers CD133, CD24, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain CSC properties. Studying such pathways may help to understand CSC biology and lead to the development of potential therapeutic interventions to render CSCs more sensitive to cell death triggered by chemotherapy and radiation therapy. Moreover, recent demonstrations of dedifferentiation of differentiated cancer cells into CSC-like cells have created significant complexity in the CSCs hypothesis. Therefore, any successful therapeutic agent or combination of drugs for cancer therapy must eliminate not only CSCs but differentiated cancer cells and the entire bulk of tumor cells. This review article expands on the CSC hypothesis and paradigm with respect to major signaling pathways and effectors that regulate CSC apoptosis resistance. Moreover, selective CSC apoptotic modulators and their therapeutic potential for making tumors more responsive to therapy are discussed. The use of novel therapies, including small-molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of CSCs, immunotherapy, and noncoding microRNAs may provide better means of treating CSCs.

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“…These transcription factors are found to be over-expressed in several of the cancers and were used to identify cancer stem cell-like cells in glioblastoma [19]. HA-CD44 interaction was proved to activate Nanog which is principally [20] involved in the stem cell maintenance and self-renewal in the ES cells [21,22].…”

Section: Ha Induces the Expression Of Pluripotent Genesmentioning

confidence: 99%

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

Vaidyanath¹,

Mahmud²,

Khayrani³

et al. 2017

J Stem Cell Res Ther

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Dedifferentiation of patient‐derived glioblastoma multiforme cell lines results in a cancer stem cell‐like state with mitogen‐independent growth

Cited by 54 publications

References 44 publications

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Resistance to Cell Death and Its Modulation in Cancer Stem Cells

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

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