Transgenic Rat Model Recreates Key Features of Human Glioblastoma

Glioblastoma (GBM) is the most common, most malignant and highest grade (grade IV) form of primary brain tumor. This quickly growing tumor invades healthy brain tissue, causing a variety of symptoms including headache, seizures, vomiting, vision problems and trouble speaking.

Treatment of GBM is challenging because safe surgical removal of the entire tumor is almost impossible and the tumor’s heterogeneous biology makes it difficult to determine which cell types would respond positively to drug interventions.

Molecular classification techniques that stratify gliomas based on specific gene expression patterns are starting to improve understanding of how important molecular features and tumor heterogeneity are in predicting GBM progression and patient response and prognosis.  Researchers are keen to use molecular techniques to generate accurate models of the large, pleomorphic tumors seen in human GBM that will make clinical imaging and intervention more relevant.

Genetically engineered mouse models have started to replace rat models of mutagen-induced transplantable cell lines because their genetic manipulability means more accurate models are achievable. However, the smaller size of the mouse brain shortens time for tumor growth, thereby limiting the clinical relevance of imaging and intervention.
To address this, Nina Connolly and colleagues from the University of Maryland School of Medicine, Baltimore, have developed a transgenic rat model that allows the formation of large, heterogenous gliomas that closely resemble those seen in human GBM.

The method they used is based on a versatile and valuable gene delivery tool called the RCAS/tv-a system. This system utilizes the fact that the replication competent avian-like sarcoma (RCAS) virus can only target cells by binding to its receptor− tumor virus A (tv-a) receptor. The tv-a gene is not present in mammalian cells, which do not express the receptor and are therefore resistant to the virus. However, by inserting the tv-a gene into cells of interest, researchers can ensure expression of the receptor and provide a port of entry for RCAS constructs.

For the current study, Connolly and team inserted the tv-a gene into rats, which was then controlled intracellularly by the nestin promoter, which is activated inside brain tumor initiating cells (BTICs). Tv-a specific RCAS plasmids that had been engineered to overexpress platelet derived growth factor subunit A (PDGFA) and deplete the tumor suppressor p53 could then enter the BTICs to induce tumor growth.

Using a state-of-the-art, high resolution BioSpec 70/30 USR 7T MR scanner from Bruker, the team generated images that showed the formation of large, heterogenous tumors. Histopathological studies showed the tumors demonstrated key characteristics seen in human GBM. Examples of these features included necrosis, microvascular proliferation, high tumor cell proliferation and lymphocyte infiltration, amongst others.

Connolly and team say this inducible rat transgenic model provides highly relevant histology and MRI for accurate modeling of tumor formation and progression in human GBM. The method may enable detailed interspecies comparison of fundamental cancer pathways and clinically relevant imaging and interventions that are not achievable with the smaller mouse brain.

• Connolly, N et al. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer. PLOS ONE 2017;12(3): e0174557.
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• Ramaswamy, V and Taylor, M. Fall of the Optical Wall: Freedom from the Tyranny of the Microscope Improves Glioma Risk Stratification. Cancer Cell 2017; 29(2); 137-138
• Hadjipanayis, C et al. Beyond the World Health Organization grading of infiltrating gliomas: advances in the molecular genetics of glioma classification. Annals of Translational Medicine 2015;3(7):95. DOI: 10.3978/j.issn.2305-5839.2015.03.57
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