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Author Munthe, S.; Halle, B.; Boldt, H.B.; Christiansen, H.; Schmidt, S.; Kaimal, V.; Xu, J.; Zabludoff, S.; Mollenhauer, J.; Poulsen, F.R.; Kristensen, B.W.
Title Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions Type Journal Article
Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol
Volume 132 Issue 1 Pages 45-54
Keywords Glioblastoma; MicroRNA; Migration; Serum-free; Target
Abstract (up) Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The miRNA profiling revealed 30 miRNAs to be differentially expressed. In total 13 miRNAs were upregulated and 17 downregulated in migrating cells compared to corresponding spheroids. The three most deregulated miRNAs, miR-1227 (up-regulated), miR-32 (down-regulated) and miR-222 (down-regulated), were experimentally overexpressed. A non-significantly increased migration rate was observed after miR-1227 overexpression. A significantly reduced migration rate was observed after miR-32 and miR-222 overexpression. In conclusion a shift in microRNA profile upon glioma cell migration was identified using an assay avoiding serum-induced migration. Both the miRNA profiling and the functional validation suggested that miR-1227 may be associated with increased migration and miR-32 and miR-222 with decreased migration. These miRNAs may represent potential novel targets in migrating glioma cells.
Address Institute of Clinical Research, University of Southern Denmark, Winslowparken 19, 5000, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk
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
Notes PMID:28091986 Approved no
Call Number ref @ user @ Serial 96611
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Author Hu, B.; Emdad, L.; Kegelman, T.P.; Shen, X.-N.; Das, S.K.; Sarkar, D.; Fisher, P.B.
Title Astrocyte Elevated Gene-1 Regulates beta-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal Type Journal Article
Year 2017 Publication Molecular Cancer Research : MCR Abbreviated Journal Mol Cancer Res
Volume 15 Issue 2 Pages 225-233
Keywords Brain Neoplasms/genetics/metabolism/*pathology; Cell Adhesion Molecules/genetics/*metabolism; Cell Line, Tumor; Glioblastoma/genetics/metabolism/*pathology; Humans; Neoplastic Stem Cells/*pathology; Signal Transduction; Tumor Cells, Cultured; beta Catenin/genetics/*metabolism
Abstract (up) Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein-protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated beta-catenin translocation into the nucleus by forming a complex with LEF1 and beta-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3beta signaling axis, AEG-1 controlled phosphorylation levels of beta-catenin that stabilized the protein. IMPLICATIONS: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225-33. (c)2016 AACR.
Address VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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 1541-7786 ISBN Medium
Area Expedition Conference
Notes PMID:27903708 Approved no
Call Number ref @ user @ Serial 96619
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Author Sareddy, G.R.; Viswanadhapalli, S.; Surapaneni, P.; Suzuki, T.; Brenner, A.; Vadlamudi, R.K.
Title Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway Type Journal Article
Year 2017 Publication Oncogene Abbreviated Journal Oncogene
Volume 36 Issue 17 Pages 2423-2434
Keywords Animals; Apoptosis/*drug effects; Cell Differentiation/*drug effects; Cell Line, Tumor; Cell Survival/drug effects; Cell Transformation, Neoplastic; Disease Progression; Enzyme Inhibitors/*pharmacology; Gene Expression Regulation, Neoplastic/drug effects; Glioma/*pathology; Histone Demethylases/*antagonists & inhibitors; Mice; Neoplastic Stem Cells/*drug effects/metabolism/pathology; Signal Transduction/drug effects; Survival Analysis; Transcription, Genetic/drug effects; Unfolded Protein Response/*drug effects
Abstract (up) Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.
Address Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, 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:27893719 Approved no
Call Number ref @ user @ Serial 96621
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Author Rosager, A.M.; Sorensen, M.D.; Dahlrot, R.H.; Boldt, H.B.; Hansen, S.; Lathia, J.D.; Kristensen, B.W.
Title Expression and prognostic value of JAM-A in gliomas Type Journal Article
Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol
Volume Issue Pages
Keywords Astrocytic brain tumors; Glioma; Junctional adhesion molecule-A; Prognosis; Tumor stem cell
Abstract (up) Gliomas are among the most lethal cancers, being highly resistant to both chemo- and radiotherapy. The expression of junctional adhesion molecule-A (JAM-A) was recently identified on the surface of stem cell-like brain tumor-initiating cells and suggested to function as a unique glioblastoma niche adhesion factor influencing the tumorigenic potential of brain tumor-initiating cells. We have recently identified high JAM-A expression to be associated with poor outcome in glioblastomas, and our aim was to further investigate the expression of JAM-A in gliomas focusing especially on the prognostic value in WHO grade II and III gliomas. JAM-A protein expression was evaluated by immunohistochemistry and advanced quantitative image analysis with continuous estimates of staining intensity. The JAM-A antibody stained tumor cell membranes and cytoplasm to various extent in different glioma subtypes, and the intensity was higher in glioblastomas than low-grade gliomas. We could not detect an association with overall survival in patients with grade II and III tumors. Double-immunofluorescence stainings in glioblastomas revealed co-expression of JAM-A with CD133, SOX2, nestin, and GFAP in tumor cells as well as some co-expression with the microglial/macrophage marker IBA-1. In conclusion, JAM-A expression was higher in glioblastomas compared to low-grade gliomas and co-localized with recognized stem cell markers suggesting an association of JAM-A with glioma aggressiveness. No significant association between JAM-A expression and overall survival was found in grade II and III gliomas. Further research is needed to determine the function and clinical impact of JAM-A in gliomas.
Address Department of Clinical Research, University of Southern Denmark, Winslowparken 19, 3rd floor, 5000, Odense, Denmark
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
Notes PMID:28677106 Approved no
Call Number ref @ user @ Serial 96579
Permanent link to this record
 

 
Author Ludwig, K.; Kornblum, H.I.
Title Molecular markers in glioma Type Journal Article
Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol
Volume Issue Pages
Keywords Glioblastoma; Glioma stem cell; Molecular markers; Mutations; Pathways
Abstract (up) Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular heterogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they may have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC's (CD133, CD15, A2B5, nestin, ALDH1, proteasome activity, ABC transporters, and label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas.
Address Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. Hkornblum@mednet.ucla.edu
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
Notes PMID:28233083 Approved no
Call Number ref @ user @ Serial 96605
Permanent link to this record