Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies.
OBJECTIVE
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.


METHODS
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 p16(Ink4a)/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.


CONCLUSIONS
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.
de Vries
Nienke A
NA
Department of Clinical Chemistry/Preclinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Bruggeman
Sophia W
SW
Hulsman
Danielle
D
de Vries
Hilda I
HI
Zevenhoven
John
J
Buckle
Tessa
T
Hamans
Bob C
BC
Leenders
William P
WP
Beijnen
Jos H
JH
van Lohuizen
Maarten
M
Berns
Anton J M
AJ
van Tellingen
Olaf
O
D020727:ADP-Ribosylation Factors / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D019942:Genes, p16; D016158:Genes, p53; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D014162:Transfection; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020727:ADP-Ribosylation Factors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins