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Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain

Translation of promising experimental therapies from rodent models to clinical success has been complicated as the novel therapies often fail in clinical trials. Existing rodent glioma models generally do not allow for preclinical evaluation of the efficiency of novel therapies in combination with s...

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Autores principales: Ahmad, Farizan, Hyvärinen, Anna, Pirinen, Agnieszka, Olsson, Venla, Rummukainen, Jaana, Immonen, Arto, Närväinen, Johanna, Tuunanen, Pasi, Liimatainen, Timo, Kärkkäinen, Virve, Koistinaho, Jari, Ylä-Herttuala, Seppo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047887/
https://www.ncbi.nlm.nih.gov/pubmed/33846766
http://dx.doi.org/10.3892/mmr.2021.12061
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author Ahmad, Farizan
Hyvärinen, Anna
Pirinen, Agnieszka
Olsson, Venla
Rummukainen, Jaana
Immonen, Arto
Närväinen, Johanna
Tuunanen, Pasi
Liimatainen, Timo
Kärkkäinen, Virve
Koistinaho, Jari
Ylä-Herttuala, Seppo
author_facet Ahmad, Farizan
Hyvärinen, Anna
Pirinen, Agnieszka
Olsson, Venla
Rummukainen, Jaana
Immonen, Arto
Närväinen, Johanna
Tuunanen, Pasi
Liimatainen, Timo
Kärkkäinen, Virve
Koistinaho, Jari
Ylä-Herttuala, Seppo
author_sort Ahmad, Farizan
collection PubMed
description Translation of promising experimental therapies from rodent models to clinical success has been complicated as the novel therapies often fail in clinical trials. Existing rodent glioma models generally do not allow for preclinical evaluation of the efficiency of novel therapies in combination with surgical resection. Therefore, the aim of the present study was to develop a larger animal model utilizing lentivirus vector-mediated oncogenic transformation in the rabbit brain. Lentiviruses carrying constitutively active AKT and H-Ras oncogenes, and p53 small interfering (si)RNA were introduced into newborn rabbit neural stem cells (NSCs) and intracranially implanted into rabbits' brains to initiate tumor formation. In one of the ten rabbits a tumor was detected 48 days after the implantation of transduced NSCs. Histological features of the tumor mimic was similar to a benign Grade II ganglioglioma. Immunostaining demonstrated that the tissues were positive for AKT and H-Ras. Strong expression of GFAP and Ki-67 was also detected. Additionally, p53 expression was notably lower in the tumor area. The implantation of AKT, H-Ras and p53 siRNA transduced NSCs for tumor induction resulted in ganglioglioma formation. Despite the low frequency of tumor formation, this preliminary data provided a proof of principle that lentivirus vectors carrying oncogenes can be used for the generation of brain tumors in rabbits. Moreover, these results offer noteworthy insights into the pathogenesis of a rare brain tumor, ganglioglioma.
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spelling pubmed-80478872021-04-16 Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain Ahmad, Farizan Hyvärinen, Anna Pirinen, Agnieszka Olsson, Venla Rummukainen, Jaana Immonen, Arto Närväinen, Johanna Tuunanen, Pasi Liimatainen, Timo Kärkkäinen, Virve Koistinaho, Jari Ylä-Herttuala, Seppo Mol Med Rep Articles Translation of promising experimental therapies from rodent models to clinical success has been complicated as the novel therapies often fail in clinical trials. Existing rodent glioma models generally do not allow for preclinical evaluation of the efficiency of novel therapies in combination with surgical resection. Therefore, the aim of the present study was to develop a larger animal model utilizing lentivirus vector-mediated oncogenic transformation in the rabbit brain. Lentiviruses carrying constitutively active AKT and H-Ras oncogenes, and p53 small interfering (si)RNA were introduced into newborn rabbit neural stem cells (NSCs) and intracranially implanted into rabbits' brains to initiate tumor formation. In one of the ten rabbits a tumor was detected 48 days after the implantation of transduced NSCs. Histological features of the tumor mimic was similar to a benign Grade II ganglioglioma. Immunostaining demonstrated that the tissues were positive for AKT and H-Ras. Strong expression of GFAP and Ki-67 was also detected. Additionally, p53 expression was notably lower in the tumor area. The implantation of AKT, H-Ras and p53 siRNA transduced NSCs for tumor induction resulted in ganglioglioma formation. Despite the low frequency of tumor formation, this preliminary data provided a proof of principle that lentivirus vectors carrying oncogenes can be used for the generation of brain tumors in rabbits. Moreover, these results offer noteworthy insights into the pathogenesis of a rare brain tumor, ganglioglioma. D.A. Spandidos 2021-06 2021-04-06 /pmc/articles/PMC8047887/ /pubmed/33846766 http://dx.doi.org/10.3892/mmr.2021.12061 Text en Copyright: © Ahmad et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Ahmad, Farizan
Hyvärinen, Anna
Pirinen, Agnieszka
Olsson, Venla
Rummukainen, Jaana
Immonen, Arto
Närväinen, Johanna
Tuunanen, Pasi
Liimatainen, Timo
Kärkkäinen, Virve
Koistinaho, Jari
Ylä-Herttuala, Seppo
Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title_full Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title_fullStr Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title_full_unstemmed Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title_short Lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
title_sort lentivirus vector-mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047887/
https://www.ncbi.nlm.nih.gov/pubmed/33846766
http://dx.doi.org/10.3892/mmr.2021.12061
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