- Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo.
Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1.
Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment.
Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
MetadatenVerfasserangaben: | Klaus Mantwill, Ulrike NaumannORCiD, Janina Seznec, Vroni Girbinger, Hermann Lage, Pawel Surowiak, Dagmar Beier, Michel Guy André MittelbronnORCiDGND, Jürgen Schlegel, Per Sonne Holm |
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URN: | urn:nbn:de:hebis:30:3-318122 |
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DOI: | https://doi.org/10.1186/1479-5876-11-216 |
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ISSN: | 1479-5876 |
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Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/24044901 |
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Titel des übergeordneten Werkes (Englisch): | Journal of translational medicine |
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Verlag: | BioMed Central |
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Verlagsort: | London |
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Dokumentart: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Datum der Veröffentlichung (online): | 18.09.2013 |
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Datum der Erstveröffentlichung: | 18.09.2013 |
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Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Datum der Freischaltung: | 21.10.2013 |
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Freies Schlagwort / Tag: | Cancer stem cells; Oncolytic virus; Temozolomide; Virotherapy; YB-1 |
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Jahrgang: | 11 |
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Ausgabe / Heft: | 216 |
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Seitenzahl: | 13 |
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Bemerkung: | © 2013 Mantwill et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
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HeBIS-PPN: | 362781575 |
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Institute: | Medizin / Medizin |
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DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Lizenz (Deutsch): | Creative Commons - Namensnennung 2.0 |
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