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.