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Author Emery, I.F.; Gopalan, A.; Wood, S.; Chow, K.-H.; Battelli, C.; George, J.; Blaszyk, H.; Florman, J.; Yun, K.
Title Expression and function of ABCG2 and XIAP in glioblastomas Type Journal Article
Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol
Volume 133 Issue 1 Pages 47-57
Keywords Abcg2; Glioblastoma; Glioma stem cells; Ko143; Xiap
Abstract Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic strategy in GBMs.
Address Peak Center for Brain and Pituitary Tumors, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030, USA. kyun@houstonmethodist.org
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 0167-594X ISBN Medium
Area Expedition Conference (down)
Notes PMID:28432589 Approved no
Call Number ref @ user @ Serial 96591
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Author Batista, K.M.P.; Eulate-Beramendi, S.A. de; Pina, K.Y.A.R. de; Figueira, P.R.; Canal, A.F.; Chasin, J.M.A.; Meilan, A.; Ugalde, R.; Vega, I.F.
Title Mesenchymal/proangiogenic factor YKL-40 related to glioblastomas and its relationship with the subventricular zone Type Journal Article
Year 2017 Publication Folia Neuropathologica Abbreviated Journal Folia Neuropathol
Volume 55 Issue 1 Pages 14-22
Keywords Ykl-40; glioblastoma; glioblastoma stem cells; subventricular zone
Abstract <i>Glioblastoma is the most common primary brain tumor. Despite multimodality therapy with aggressive microsurgical resection and adjuvant chemotherapy and radiotherapy, the median survival is below 15 months. Glioblastomas are heterogeneous tumors with high resistance to most chemotherapeutic drugs. According to reliable evidence, YKL-40, one of the best investigated chitinase-like protein, may facilitate invasion, migration and angiogenesis, and could be also responsible for temozolomide resistance in glioblastoma, thus conferring a dismal prognosis. Previous studies have demonstrated that glioblastoma stem cells give rise to endothelial cells through an YKL-40 influence. Such factor is closely related to the subventricular zone. This review focuses on the most recent theories involving the possible relationship between topographic gliomagenesis related to the subventricular zone and YKL-40.</i>.
Address
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 1509-572X ISBN Medium
Area Expedition Conference (down)
Notes PMID:28430288 Approved no
Call Number ref @ user @ Serial 96592
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Author Khalifa, J.; Tensaouti, F.; Lusque, A.; Plas, B.; Lotterie, J.-A.; Benouaich-Amiel, A.; Uro-Coste, E.; Lubrano, V.; Cohen-Jonathan Moyal, E.
Title Subventricular zones: new key targets for glioblastoma treatment Type Journal Article
Year 2017 Publication Radiation Oncology (London, England) Abbreviated Journal Radiat Oncol
Volume 12 Issue 1 Pages 67
Keywords Glioblastoma; Prognostic factors; Radiotherapy; Stem-cell niche; Subventricular Zone
Abstract BACKGROUND: We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. METHODS: Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). RESULTS: Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively). CONCLUSION: Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.
Address INSERM U1037, Centre de Recherche contre le Cancer de Toulouse, 1 avenue Irene Joliot-Curie, Toulouse Cedex, 31059, France
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 1748-717X ISBN Medium
Area Expedition Conference (down)
Notes PMID:28424082 Approved no
Call Number ref @ user @ Serial 96593
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Author Brodie, S.; Lee, H.K.; Jiang, W.; Cazacu, S.; Xiang, C.; Poisson, L.M.; Datta, I.; Kalkanis, S.; Ginsberg, D.; Brodie, C.
Title The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 19 Pages 31785-31801
Keywords Talnec2; glioblastoma; glioma stem cells; long non-cording RNAs; mesenchymal transformation
Abstract Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.
Address Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, 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 1949-2553 ISBN Medium
Area Expedition Conference (down)
Notes PMID:28423669 Approved no
Call Number ref @ user @ Serial 96594
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Author Sullivan, K.E.; Rojas, K.; Cerione, R.A.; Nakano, I.; Wilson, K.F.
Title The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 14 Pages 22325-22343
Keywords Aldehyde Oxidoreductases/genetics/*metabolism; Biomarkers, Tumor/metabolism; Brain Neoplasms/genetics/*metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine/analogs & derivatives/pharmacology; GTP-Binding Proteins/genetics/*metabolism; Gene Expression Regulation, Neoplastic; Glioma/genetics/*metabolism; Humans; Mesenchymal Stromal Cells/*physiology; Neoplastic Stem Cells/*physiology; RNA, Small Interfering/genetics; Stem Cells/*physiology; Transglutaminases/genetics/*metabolism; Tretinoin/metabolism; Up-Regulation; aldehyde dehydrogenase; cancer stem cells; glioblastoma; retinoic acid; tissue transglutaminase
Abstract Tissue transglutaminase (tTG), a dual-function enzyme with GTP-binding and acyltransferase activities, has been implicated in the survival and chemotherapy resistance of aggressive cancer cells and cancer stem cells, including glioma stem cells (GSCs). Using a model system comprising two distinct subtypes of GSCs referred to as proneural (PN) and mesenchymal (MES), we find that the phenotypically aggressive and radiation therapy-resistant MES GSCs exclusively express tTG relative to PN GSCs. As such, the self-renewal, proliferation, and survival of these cells was sensitive to treatment with tTG inhibitors, with a benefit being observed when combined with the standard of care for high grade gliomas (i.e. radiation or temozolomide). Efforts to understand the molecular drivers of tTG expression in MES GSCs revealed an unexpected link between tTG and a common marker for stem cells and cancer stem cells, Aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3, as well as other members of the ALDH1 subfamily, can function in cells as a retinaldehyde dehydrogenase to generate retinoic acid (RA) from retinal. We show that the enzymatic activity of ALDH1A3 and its product, RA, are necessary for the observed expression of tTG in MES GSCs. Additionally, the ectopic expression of ALDH1A3 in PN GSCs is sufficient to induce the expression of tTG in these cells, further demonstrating a causal link between ALDH1A3 and tTG. Together, these findings ascribe a novel function for ALDH1A3 in an aggressive GSC phenotype via the up-regulation of tTG, and suggest the potential for a similar role by ALDH1 family members across cancer types.
Address Department of Molecular Medicine, Cornell University, Ithaca, NY, 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 1949-2553 ISBN Medium
Area Expedition Conference (down)
Notes PMID:28423611 Approved no
Call Number ref @ user @ Serial 96595
Permanent link to this record