Lentiviral-Induced High-Grade Gliomas in Rats: The Effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H
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In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics.
Key WordsGene therapy HSV1-TK adenoviral vectors brain tumors
This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) grants 1RO1-NS 054193, 1RO1-NS 061107, and 1RO1-NS082311 to P.R.L.; and grants 1UO1-NS052465, 1RO1-NS 057711, and 1RO1-NS074387 to M.G.C. We thank Drs. I. Verma, E.C. Holland, and P. Canoll for providing valuable expression vectors utilized in this work. We thank Mr. Philip Jenkins and the Department of Neurosurgery at the University of Michigan, School of Medicine for their support of our work. We also thank Dr. Karin Murasko for her academic leadership, and D. Tomford and S. Napolitan for superb administrative support. The schematic of tumor infiltration (Fig. 4G) was created by Alan Traxler (email@example.com). Full conflict of interest disclosure is available in the electronic supplementary material for this article.
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