Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression1,2,3. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas4,5. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo6,7,8,9,10). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.
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We thank D. Crowley, N.H. Fong, K. Mercer and B. Williams for technical assistance; A. Charest, J. Sage, K. Cichowski, K. Olive, K. Johnson, K. Tsai and D. Tuveson for discussions; C. Whittaker, C. Fry, M. Bryce and J. Reilly for assistance in preparation of the manuscript and figures; and S. Shih for assistance with inbreeding of Nf1+/− mice. K.M.R. is supported by a post-doctoral fellowship from the Leukemia & Lymphoma Society. T.J. is an Associate Investigator of the Howard Hughes Medical Institute. This work was supported in part by a grant from the Department of the Army and the Medallion Foundation.
Tumor phenotype of NPcis miceThe table summarizes for the mice in this study the sex; strain background (background); generation (gen); age at time of death (age); description of tumor histology as scored by atypical nuclei (AN), mitotic figures (M), presence of a focal tumor (FT), necrosis (N), excessive or aberrant blood vessels (V), multinucleated giant cells (GC), and spread to the leptomeninges (LM); grade of tumor based on the grading criteria described in figure 6 legend (grade); immunoreactivity for GFAP, synaptophysin (SNPN), and nestin; the number of days the animal was monitored from the time it was noticed to be sick to the time of sacrifice (days to sac); the observations at the time of sacrifice (reason for sacrifice); whether other tumor types were present (other tumors); and location of tumor (location). The age of the mice is given in months. Immunoreactivity for GFAP is indicated by "+++" for widespread staining of tumor cells, "++" for staining of sparse tumor cells within the tumor, "+" for cells staining within the tumor that could not be distinguished from reactive astrocytes. Tumors scored "+" for GFAP may contain positive staining tumor cells; however, the morphology of the stained cells did not allow us to determine whether the cells were tumor cells or normal cells. Immunoreactivity for synaptophysin is indicated by "-" for no positive cells within the tumor and "+/-" for tumors showing staining of normal neurons within the region of the tumor. These tumors were located in the olfactory bulb or pons and had invaded regions of dense neuronal processes. No tumor showed immunoreactivity for nestin. It should be noted that for the purposes of this study any mouse showing signs of neurological impairment was sacrificed immediately; therefore the days to sacrifice cannot be taken as a measure of brain tumor progression. The mice that were followed for long periods of time showed slow growing, externally visible soft tissue sarcomas. The mice listed under Laser Captured Samples and Additional Tumor Cell Line Samples were not from the same sibling set as the mice in the upper section of the table. They were not included in the calculation of penetrance of the phenotype or in the percentage of tumors immunoreative for GFAP. Cell lines were also generated from KR158 (B6) and KR130 (SXB6). Within each strain group the mice are listed in order from youngest at time of death to oldest. The B6, HXB6, and SXB6 all show a clear trend towards higher grade tumors in older mice and 90-100% penetrance of brain tumors after 6 months of age.
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Journal of Neuro-Oncology (2017)