Rapid and Robust Transgenic High-Grade Glioma Mouse Models for Therapy Intervention Studies

Abstract

Purpose: To develop a transgenic mouse model of glioma that can be conveniently used for testing therapy intervention strategies. High-grade glioma is a devastating and uniformly fatal disease for which better therapy is urgently needed. Typical for high-grade glioma is that glioma cells infiltrate extensively into surrounding pivotal brain structures, thereby rendering current treatments largely ineffective. Evaluation of novel therapies requires the availability of appropriate glioma mouse models.Experimental Design: High-grade gliomas were induced by stereotactic intracranial injection of lentiviral GFAP-Cre or CMV-Cre vectors into compound LoxP-conditional mice, resulting in K-Ras v12 expression and loss of p16Ink4a /p19 Arf with or without concomitant loss of p53 or Pten.Results: Tumors reproduced many of the features that are characteristic for human high-grade gliomas, including invasiveness and blood-brain barrier functionality. Especially, CMV-Cre injection into p53; Ink4a/Arf;K-Ras v12 mice resulted in high-grade glioma with a short tumor latency (2-3 weeks) and full penetrance. Early detection and follow-up was accomplished by noninvasive bioluminescence imaging, and the practical utility for therapy intervention was shown in a study with temozolomide. Conclusion:We have developed a realistic high-grade glioma model that can be used with almost the same convenience as traditional xenograft models, thus allowing its implementation at the forefront of preclinical evaluation of new treatments. Clin Cancer Res; 16(13); 3431-41. ©2010 AACR.

Lentiviral-Induced High-Grade Gliomas in Rats: The Effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H

“…In order to reach these practical goals for de novo glioma modeling in mice, genetic alterations decreasing the efficacy of the TP53 and RB tumor suppressor genes have been necessary [16,17,23,25,27,28]. In rats, our data confirm the results of Assanah et al [18], suggesting that the need for p53 inactivation in glioma may be speciesdependent, and that the manipulation of the RTK/RAS/ PI(3)K signaling pathway is sufficient to create gliomas in rats.…”

“…Previous animal models (Table 2) have been built on manipulations of the RTK/PI3K/HRAS-G12V (i.e., proliferative) signaling pathway in order to reliably create tumors in mice and rats [17][18][19][23][24][25][26][27][28]. In previous animal models, while deletion of PTEN is clearly an important driver, addition of oncogenic AKT and RAS are frequently required in combination with each other or with alterations p53 or RB signaling for tumor formation.…”

Assessment of Rodent Glioma Models Using Magnetic Resonance Imaging Techniques

“…By inhibiting PDGFR activity, it was possible to convert tumors from high to low grade (Shih et al, 2004). Another recent study involved intracranial injection of lentiviral vectors with GFAP (glial fibrially acidic protein) or CMV (cytomegalovirus) vectors into compound LoxP-conditional mice, which resulted in K-Ras v12 expression and loss of p16 Ink4a /p19 Arf , with or without concomitant loss of p53 or Pten (de Vries et al, 2010). Like GFAP, CMV is a promoter (de Vries et al, 2010).…”

“…Another recent study involved intracranial injection of lentiviral vectors with GFAP (glial fibrially acidic protein) or CMV (cytomegalovirus) vectors into compound LoxP-conditional mice, which resulted in K-Ras v12 expression and loss of p16 Ink4a /p19 Arf , with or without concomitant loss of p53 or Pten (de Vries et al, 2010). Like GFAP, CMV is a promoter (de Vries et al, 2010). CMV-Cre injection into p53;Ink4a/Arf;K-Ras v12 mice was particularly found to result in the formation of high-grade gliomas within 2-3 weeks that had invasiveness and blood-brain barrier functionality characteristics that are found in human high-grade gliomas (de Vries et al, 2010).…”

“…Like GFAP, CMV is a promoter (de Vries et al, 2010). CMV-Cre injection into p53;Ink4a/Arf;K-Ras v12 mice was particularly found to result in the formation of high-grade gliomas within 2-3 weeks that had invasiveness and blood-brain barrier functionality characteristics that are found in human high-grade gliomas (de Vries et al, 2010).…”