Genetic modeling of gliomas in mice: New tools to tackle old problems

Abstract

The recently published comprehensive profiles of genomic alterations in glioma have led to a refinement in our understanding of the molecular events that underlie this cancer. Using state-of-the-art genomic tools, several laboratories have created and characterized accurate genetically engineered mouse models of glioma based on specific genetic alterations observed in human tumors. These in vivo brain tumor models faithfully recapitulate the histopathology, etiology, and biology of gliomas and provide an exceptional experimental system to discover novel therapeutic targets and test therapeutic agents. This review focuses on mouse models of glioma with a special emphasis on genetically engineered models developed around key genetic glioma signature mutations in the PDGFR, EGFR and NF1 genes and pathways. The resulting animal models have provided insight into many fundamental and mechanistic facets of tumor initiation, maintenance and resistance to therapeutic intervention and will continue to do so in the future.

Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation

“…Cultured cell lines, xenografts and genetically engineered mice are the most common methods for modeling gliomas, and there are distinct benefits and limitations for each model system 3,13,14 . Relevant benefits of primary orthotopic glioma xenografts include infiltrative growth that typifies diffuse gliomas and the retention of genetic alterations and important signaling mechanisms that can be exceedingly difficult to maintain in cultured glioma cells.…”

“…Relevant benefits of primary orthotopic glioma xenografts include infiltrative growth that typifies diffuse gliomas and the retention of genetic alterations and important signaling mechanisms that can be exceedingly difficult to maintain in cultured glioma cells. For example, isocitrate dehydrogenase mutations and Sonic hedgehog ligand production can be maintained in primary orthotopic xenografts 15,16 but only rarely in cultured glioma cells 14,[17][18][19] . It is important to consider significant disadvantages of primary orthotopic xenografts, however, depending upon experimental needs.…”

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

“…Fortunately, histologically and genetically relevant mouse models of GBM that correspond with the molecular subtypes have already been developed and these models validate the significance of signal transduction pathways in gliomagenesis (Zhu et al, 2009;Hambardzumyan et al, 2011;Jones and Holland, 2011). There are several short latency and high penetrant models that can be used to better understand the biology of glioma and are essential tools for testing novel drugs against this terminal disease.…”

EGFR signaling in the brain is necessary for olfactory learning in Drosophila larvae

“…As one of the major signaling pathways involved in tumor growth and metastasis, it has been extensively studied in mammalian cells and numerous animal models (Arteaga 2006;Hambardzumyan et al 2011;Mimeault and Batra 2011;Read 2011). Excessive EGFR signaling has been causally linked to the development of various cancers (Moasser 2007;Harris and McCormick 2010;Hatanpaa et al 2010).…”