Immunohistochemical Characterization and Sensitivity to Human Adenovirus Serotypes 3, 5, and 11p of New Cell Lines Derived from Human Diffuse Grade II to IV Gliomas |
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Authors: | Minna Niittykoski Mikael von und zu Fraunberg Miika Martikainen Tuomas Rauramaa Arto Immonen Susanna Koponen Ville Leinonen Markus Vähä-Koskela Qiwei Zhang Florian Kühnel Ya-Fang Mei Seppo Ylä-Herttuala Juha E. Jääskeläinen Ari Hinkkanen |
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Affiliation: | 2. NeuroCenter of Kuopio University Hospital, Kuopio, Finland;3. Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland;4. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden;5. Pathology, Institute of Clinical Medicine, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, Kuopio, Finland;11. Department of Gastroenterology, Hepatology and Endocrinology, Medical School, Hannover, Germany;12. Department of Clinical Microbiology, Umeå University, Umeå, Sweden |
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Abstract: | BACKGROUND: Oncolytic adenoviruses show promise in targeting gliomas because they do not replicate in normal brain cells. However, clinical responses occur only in a subset of patients. One explanation could be the heterogenic expression level of virus receptors. Another contributing factor could be variable activity of tumor antiviral defenses in different glioma subtypes. METHODS: We established a collection of primary low-passage cell lines from different glioma subtypes (3 glioblastomas, 3 oligoastrocytomas, and 2 oligodendrogliomas) and assessed them for receptor expression and sensitivity to human adenovirus (HAd) serotypes 3, 5, and 11p. To gauge the impact of antiviral defenses, we also compared the infectivity of the oncolytic adenoviruses in interferon (IFN)-pretreated cells with IFN-sensitive Semliki Forest virus (SFV). RESULTS: Immunostaining revealed generally low expression of HAd5 receptor CAR in both primary tumors and derived cell lines. HAd11p receptor CD46 levels were maintained at moderate levels in both primary tumor samples and derived cell lines. HAd3 receptor DSG-2 was reduced in the cell lines compared to the tumors. Yet, at equal multiplicities of infection, the oncolytic potency of HAd5 in vitro in tumor-derived cells was comparable to HAd11p, whereas HAd3 lysed fewer cells than either of the other two HAd serotypes in 72 hours. IFN blocked replication of SFV, while HAds were rather unaffected. CONCLUSIONS: Adenovirus receptor levels on glioma-derived cell lines did not correlate with infection efficacy and may not be a relevant indicator of clinical oncolytic potency. Adenovirus receptor analysis should be preferentially performed on biopsies obtained perioperatively. |
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Keywords: | Address all correspondence to: Minna Niittykoski Developmental Biology Program Institute of Biotechnology University of Helsinki P.O. Box 56 FIN-00014 Finland. |
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