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Author Guerrero, P.A.; Tchaicha, J.H.; Chen, Z.; Morales, J.E.; McCarty, N.; Wang, Q.; Sulman, E.P.; Fuller, G.; Lang, F.F.; Rao, G.; McCarty, J.H.
Title Glioblastoma stem cells exploit the alphavbeta8 integrin-TGFbeta1 signaling axis to drive tumor initiation and progression Type Journal Article
Year 2017 Publication Oncogene Abbreviated Journal Oncogene
Volume Issue Pages
Keywords
Abstract Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin alphavbeta8 and its latent transforming growth factor beta1 (TGFbeta1) protein ligand have central roles in promoting niche co-option and GBM initiation. alphavbeta8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of beta8high cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that alphavbeta8 integrin regulates tumor development, in part, by driving TGFbeta1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the alphavbeta8 integrin-TGFbeta1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.Oncogene advance online publication, 7 August 2017; doi:10.1038/onc.2017.248.
Address Department of Neurosurgery, M. D. Anderson Cancer Center, Houston, TX, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0950-9232 ISBN Medium
Area Expedition Conference
Notes PMID:28783169 Approved no
Call Number ref @ user @ Serial (up) 96572
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Author Magrath, J.W.; Kim, Y.
Title Salinomycin's potential to eliminate glioblastoma stem cells and treat glioblastoma multiforme (Review) Type Journal Article
Year 2017 Publication International Journal of Oncology Abbreviated Journal Int J Oncol
Volume 51 Issue 3 Pages 753-759
Keywords
Abstract Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain tumor. Despite treatment with surgery, radiotherapy, and chemotherapy with the drug temozolomide, the expected survival after diagnosis remains low. The median survival is only 14.6 months and the two-year survival is a mere 30%. One reason for this is the heterogeneity of GBM including the presence of glioblastoma cancer stem cells (GSCs). GSCs are a subset of cells with the unique ability to proliferate, differentiate, and create tumors. GSCs are resistant to chemotherapy and radiation and thought to play an important role in recurrence. In order to effectively treat GBM, a drug must be identified that can kill GSCs. The ionophore salinomycin has been shown to kill cancer stem cells and is therefore a promising future treatment for GBM. This study focuses on salinomycin's potential to treat GBM including its ability to reduce the CSC population, its toxicity to normal brain cells, its mechanism of action, and its potential for combination treatment.
Address Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487-0203, USA
Corporate Author Thesis
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Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1019-6439 ISBN Medium
Area Expedition Conference
Notes PMID:28766685 Approved no
Call Number ref @ user @ Serial (up) 96573
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Author Miranda, A.; Blanco-Prieto, M.; Sousa, J.; Pais, A.; Vitorino, C.
Title Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches Type Journal Article
Year 2017 Publication International Journal of Pharmaceutics Abbreviated Journal Int J Pharm
Volume 531 Issue 1 Pages 372-388
Keywords Glioblastoma; Molecular mechanisms; Temozolomide; Therapeutic advances; Therapeutic resistance
Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1-2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier. The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival. In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.
Address Faculty of Pharmacy, University of Coimbra, Portugal; Pharmacometrics Group of the Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Portugal. Electronic address: csvitorino@ff.uc.pt
Corporate Author Thesis
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Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0378-5173 ISBN Medium
Area Expedition Conference
Notes PMID:28755993 Approved no
Call Number ref @ user @ Serial (up) 96574
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Author Yin, J.; Oh, Y.T.; Kim, J.-Y.; Kim, S.S.; Choi, E.; Kim, T.H.; Hong, J.H.; Chang, N.; Cho, H.J.; Sa, J.K.; Kim, J.C.; Kwon, H.J.; Park, S.; Lin, W.; Nakano, I.; Gwak, H.-S.; Yoo, H.; Lee, S.-H.; Lee, J.; Kim, J.H.; Kim, S.-Y.; Nam, D.-H.; Park, M.-J.; Park, J.B.
Title Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPbeta Signaling Type Journal Article
Year 2017 Publication Cancer Research Abbreviated Journal Cancer Res
Volume 77 Issue 18 Pages 4973-4984
Keywords
Abstract Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPbeta, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kappaB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPbeta expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. (c)2017 AACR.
Address Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0008-5472 ISBN Medium
Area Expedition Conference
Notes PMID:28754668 Approved no
Call Number ref @ user @ Serial (up) 96575
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Author Behling, F.; Kaltenstadler, M.; Noell, S.; Schittenhelm, J.; Bender, B.; Eckert, F.; Tabatabai, G.; Tatagiba, M.; Skardelly, M.
Title The Prognostic Impact of Ventricular Opening in Glioblastoma Surgery: A Retrospective Single Center Analysis Type Journal Article
Year 2017 Publication World Neurosurgery Abbreviated Journal World Neurosurg
Volume 106 Issue Pages 615-624
Keywords Extent of resection; Glioblastoma; Hydrocephalus; Overall survival; Prognosis; Tumor volume; Ventricle opening
Abstract OBJECTIVE: Ventricular opening during glioblastoma (GBM) resection is controversial. Sufficient evidence regarding its prognostic role is missing. We investigated the impact of ventricular opening on overall survival (OS), hydrocephalus development, and postoperative morbidity in patients with GBM. METHODS: Patients who underwent primary GBM resection between 2006 and 2013 were assessed retrospectively. Established predictors for overall survival (age, Karnofsky Performance Status, extent of resection, O-6-methylguanine-DNA methyltransferase promoter methylation status, isocitrate dehydrogenase mutation status) and further clinical data (postoperative status, further treatment, preoperative tumor volume, proximity to the ventricle) were included in univariate and multivariate analyses. RESULTS: Thirteen (5.7%) of 229 patients developed a hydrocephalus. Multivariate logistic regression showed that neither ventricular opening, tumor size, proximity to the ventricle, nor extent of resection were significant risk factors for hydrocephalus. Ventricular opening did not delay postoperative therapy and was not associated with neurological morbidity. Kaplan-Meier analysis demonstrated that patients who underwent ventricular opening (n = 114) exhibited a median OS of 14.3 months (12.9-16.5), whereas patients who did not undergo ventricular opening (n = 115) exhibited a median OS of 18.6 months (16.1-20.8). However, multivariate Cox regression (n = 134) did not confirm ventricular opening as an independent negative predictor of OS (risk ratio 1.09, P = 0.77). Instead, it showed that a greater preoperative tumor volume >22.8 cm3 was a negative predictor of OS (risk ratio 1.76, P = 0.02). CONCLUSIONS: Because extent of resection is a strong independent predictor of OS and ventricular opening is safe, neurosurgeons should consider ventricular opening to achieve maximal tumor resection.
Address Department of Neurosurgery, University Hospital Tuebingen, Eberhard Karls University, Tuebingen, Germany; Center for CNS Tumors, Comprehensive Cancer Center Tuebingen Stuttgart, University Hospital Tuebingen, Eberhard Karls University, Tuebingen, Germany
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1878-8750 ISBN Medium
Area Expedition Conference
Notes PMID:28729143 Approved no
Call Number ref @ user @ Serial (up) 96576
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