title: Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.
abstract: Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor-associated microglia- and bone marrow-derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nina P
authors.identifier: http://orcid.org/0000-0003-0498-6148
authors.initials: NP
authors.lastname: Connolly
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Stokum
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Schneider
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Su
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Galisteo
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Rudolph J
authors.initials: RJ
authors.lastname: Castellani
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.affiliation: Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
mesh_terms: D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics / Q000472:pathogenicity; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005818:Genetic Engineering; D005910:Glioma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000821:virology; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D064231:Nestin / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D051381:Rats; D055647:Rats, Transgenic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C577486:Nes protein, rat; D064231:Nestin; D010982:Platelet-Derived Growth Factor; D016159:Tumor Suppressor Protein p53; C075278:platelet-derived growth factor A