title: Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H.
abstract: 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.
authors.affiliation: Department of Neurosurgery, University of Michigan, School of Medicine, 4570 MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lynes
authors.forename: Mia
authors.initials: M
authors.lastname: Wibowo
authors.forename: Carl
authors.initials: C
authors.lastname: Koschmann
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Baker
authors.forename: Vandana
authors.initials: V
authors.lastname: Saxena
authors.forename: A K M G
authors.initials: AK
authors.lastname: Muhammad
authors.forename: Niyati
authors.initials: N
authors.lastname: Bondale
authors.forename: Julia
authors.initials: J
authors.lastname: Klein
authors.forename: Hikmat
authors.initials: H
authors.lastname: Assi
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
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