title: Natural history of meningioma development in mice reveals: a synergy of Nf2 and p16(Ink4a) mutations.
abstract: Meningiomas account for approximately 30% of all primary central nervous system tumors and are found in half of neurofibromatosis type 2 patients often causing significant morbidity. Although most meningiomas are benign, 10% are classified as atypical or anaplastic, displaying aggressive clinical behavior. Biallelic inactivation of the neurofibromatosis 2 (NF2) tumor suppressor is associated with meningioma formation in all NF2 patients and 60% of sporadic meningiomas. Deletion of the p16(INK4a)/p14(ARF) locus is found in both benign and malignant meningiomas, while mutation of the p53 tumor suppressor gene is uncommon. Previously, we inactivated Nf2 in homozygous conditional knockout mice by adenoviral Cre delivery and showed that Nf2 loss in arachnoid cells is rate-limiting for meningioma formation. Here, we report that additional nullizygosity for p16(Ink4a) increases the frequency of meningioma and meningothelial proliferation in these mice without modifying the tumor grade. In addition, by using magnetic resonance imaging (MRI) to screen a large cohort of mutant mice, we were able to detect meningothelial proliferation and meningioma development opening the way to future studies in which therapeutic interventions can be tested as preclinical assessment of their potential clinical application.
authors.affiliation: Inserm U674, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Kalamarides
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Han
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chareyre
authors.forename: Michiko
authors.initials: M
authors.lastname: Niwa-Kawakita
authors.forename: Peter M
authors.initials: PM
authors.lastname: Black
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008579:Meningioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D016518:Neurofibromatosis 2 / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D025581:Neurofibromin 2 / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025581:Neurofibromin 2