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Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation

Oncogene volume 32, pages 4264–4272 (2013)Cite this article

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Abstract

Aggressive variants of meningiomas (WHO grade II and III) represent up to 30% of those tumors that are among the most common primary central nervous system tumors in adults. Currently, there is no effective treatment for grade-II and -III meningiomas, the main treatment remaining surgical excision. Genetic studies have highlighted two main events associated with meningioma progression: an increase of chromosomal instability in tumors with NF2 inactivation and homozygous deletions or point mutations of the CDKN2AB locus. In this study we demonstrated that in mice, in addition to bi-allelic Nf2 inactivation, homozygous and heterozygous Adenovirus Cre-mediated Cdkn2ab deletions lead to increased meningioma frequency (72% and 50%, respectively) with a shorter latency (3.5 and 7.8 months, respectively) compared with control cohorts and induce grade II/III meningioma progression with an incidence of 34% and 28%, respectively. Moreover, Cdkn2ab inactivation in arachnoidal cells was associated with decreased senescence compared with Nf2−/− and wild-type arachnoidal cells in vitro. We have established three mouse meningioma cell lines and generated a syngenic orthotopic meningioma mouse model with 50–100% grade-II/III meningiomas after reimplantation. Comparative genomic hybridization of four meningiomas from Cdkn2ab homozygous mice and three cell cultures revealed the absence of unbalanced chromosomal segments in tumors and several chromosome imbalances in cell cultures. In addition, we were able to detect meningiomas by using bioluminescence and to evaluate tumor vascular permeability by dynamic magnetic resonance imaging. These results show that Nf2 and Cdkn2ab cooperate to promote meningioma progression in mice. The short latency of tumor development and the ability to derive grade II/III meningioma cell cultures are key aspects of this model to promote its use in pre-clinical drug testing.

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Acknowledgements

We thank A Berns for Ink4ab−/+ mutant mice, M Pla and staff of the Institut Universitaire d’Hematologie (IUH), Universite Paris 7, for mouse housing. We also thank J Calderaro and G Morcrette for their help in additional pathological analyses. This work was supported by Grants from the Association pour la Recherche sur le Cancer (subvention fixe and funding to MP), Ligue Nationale contre le Cancer-comité Paris, Fondation Anber, Association Neurofibromatoses et Recklinghausen (to ECT and NK) and Inserm.

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Authors and Affiliations

  1. Department of Neurosurgery, AP-HP, Hopital Beaujon, Clichy, France

    M Peyre & M Kalamarides

  2. Université Paris 7—Denis Diderot, Paris, France

    M Peyre, E Clermont-Taranchon, M Niwa-Kawakita, N Karboul & M Kalamarides

  3. Unité Inserm U674, Fondation Jean Dausset, Paris, France

    M Peyre, E Clermont-Taranchon, M Niwa-Kawakita, N Karboul & M Kalamarides

  4. Department of Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    A Stemmer-Rachamimov

  5. Institut national de la santé et de la recherche médicale (INSERM), U944, Institut Universitaire d’Hématologie, Paris, France

    S Quentin

  6. Institut national de la santé et de la recherche médicale (INSERM), U759, Orsay, France

    N El-Taraya, C Walczak & A Volk

  7. Institut Curie, Centre de Recherche, Orsay, France

    N El-Taraya, C Walczak & A Volk

  8. House Research Institute, Los Angeles, CA, USA

    M Giovannini

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Peyre, M., Stemmer-Rachamimov, A., Clermont-Taranchon, E. et al. Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation. Oncogene 32, 4264–4272 (2013). https://doi.org/10.1038/onc.2012.436

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