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

doi:10.3892/mmr.2021.12061

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

Authors:
- Farizan Ahmad
- Anna Hyvärinen
- Agnieszka Pirinen
- Venla Olsson
- Jaana Rummukainen
- Arto Immonen
- Johanna Närväinen
- Pasi Tuunanen
- Timo Liimatainen
- Virve Kärkkäinen
- Jari Koistinaho
- Seppo Ylä‑Herttuala
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Affiliations: A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI‑70211 Kuopio, Finland, Department of Pathology, Kuopio University Hospital, FI‑70029 Kuopio, Finland, Department of Neurosurgery, Neurocenter in Kuopio University Hospital, FI‑70029 Kuopio, Finland
Published online on: April 6, 2021 https://doi.org/10.3892/mmr.2021.12061
Article Number: 422
Copyright: © Ahmad et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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