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Published on: September 12, 2019
Lentivirus vector‑mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain
Farizan Ahmad1, Anna Hyvärinen1, Agnieszka Pirinen1
1A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI‑70211 Kuopio, Finland.
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.
Insights
Researchers developed a novel rabbit brain tumor model using lentiviral vectors to study ganglioglioma. This larger animal model shows promise for preclinical evaluation of new therapies, overcoming limitations of rodent models for brain tumor research.
Area of Science:
- Oncology
- Neuroscience
- Gene Therapy
Background:
- Rodent models for glioma research have limitations in predicting clinical success of novel therapies.
- Preclinical evaluation of combination therapies, including surgical resection, is challenging with existing rodent glioma models.
Purpose of the Study:
- To develop a larger animal model for brain tumor research using rabbits.
- To utilize lentivirus vector-mediated oncogenic transformation for inducing brain tumors in rabbits.
Main Methods:
- Lentiviruses encoding AKT, H-Ras oncogenes, and p53 siRNA were used to transduce rabbit neural stem cells (NSCs).
- Transduced NSCs were intracranially implanted into newborn rabbits to induce tumor formation.
- Tumor development was monitored, and resulting tissues were analyzed via histology and immunostaining.
Main Results:
- A ganglioglioma, mimicking a benign Grade II tumor, formed in one of ten rabbits 48 days post-implantation.
- Immunostaining confirmed expression of AKT, H-Ras, GFAP, and Ki-67, with reduced p53 expression in the tumor.
- This study demonstrated proof of principle for generating brain tumors in rabbits using lentiviral vectors.
Conclusions:
- Lentivirus vector-mediated oncogene delivery can generate brain tumors in a larger animal model (rabbits).
- This rabbit model offers potential for preclinical evaluation of novel brain tumor therapies.
- The findings provide insights into the pathogenesis of ganglioglioma, a rare brain tumor.
