title: PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss.
abstract: The role of PDGF-B and its receptor in meningeal tumorigenesis is not clear. We investigated the role of PDGF-B in mouse meningioma development by generating autocrine stimulation of the arachnoid through the platelet-derived growth factor receptor (PDGFR) using the RCAStv-a system. To specifically target arachnoid cells, the cells of origin of meningioma, we generated the PGDStv-a mouse (Prostaglandin D synthase). Forced expression of PDGF-B in arachnoid cells in vivo induced the formation of Grade I meningiomas in 27% of mice by 8 months of age. In vitro, PDGF-B overexpression in PGDS-positive arachnoid cells lead to increased proliferation.We found a correlation of PDGFR-B expression and NF2 inactivation in a cohort of human meningiomas, and we showed that, in mice, Nf2 loss and PDGF over-expression in arachnoid cells induced meningioma malignant transformation, with 40% of Grade II meningiomas. In these mice, additional loss of Cdkn2ab resulted in a higher incidence of malignant meningiomas with 60% of Grade II and 30% of Grade III meningiomas. These data suggest that chronic autocrine PDGF signaling can promote proliferation of arachnoid cells and is potentially sufficient to induce meningiomagenesis. Loss of Nf2 and Cdkn2ab have synergistic effects with PDGF-B overexpression promoting meningioma malignant transformation.
authors.affiliation: Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|Université Paris 6 - Pierre et Marie Curie, Paris, France.|CRICM INSERM U1127 CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Peyre
authors.affiliation: Université Paris 6 - Pierre et Marie Curie, Paris, France.|CRICM INSERM U1127 CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Salaud
authors.affiliation: Université Paris 6 - Pierre et Marie Curie, Paris, France.|CRICM INSERM U1127 CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Clermont-Taranchon
authors.affiliation: Inserm U944, CNRS U7212, Université Paris VII, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Michiko
authors.initials: M
authors.lastname: Niwa-Kawakita
authors.affiliation: Department of Neurosurgery, AP-HP, Hôpital Beaujon, Clichy, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Goutagny
authors.affiliation: Department of Neuropathology, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.affiliation: Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|Université Paris 6 - Pierre et Marie Curie, Paris, France.|CRICM INSERM U1127 CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Kalamarides
mesh_terms: D000818:Animals; D001099:Arachnoid / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008577:Meningeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C417743:Cdkn2a protein, mouse; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D054834:Lipocalins; D020574:Proto-Oncogene Proteins c-sis; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: Nf2; PDGF; RCAS; meningioma; mouse model