PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss
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Matthieu Peyre1,2,3, Céline Salaud2,3, Estelle Clermont-Taranchon2,3, Michiko Niwa-Kawakita4, Stephane Goutagny5, Christian Mawrin6, Marco Giovannini7, Michel Kalamarides1,2,3
1Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
2Université Paris 6 - Pierre et Marie Curie, Paris, France
3CRICM INSERM U1127 CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France
4Inserm U944, CNRS U7212, Université Paris VII, Institut Universitaire d’Hématologie, Paris, France
5Department of Neurosurgery, AP-HP, Hôpital Beaujon, Clichy, France
6Department of Neuropathology, Otto-von-Guericke Universität, Magdeburg, Germany
7Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
Michel Kalamarides, e-mail: [email protected]
Keywords: meningioma, PDGF, Nf2, mouse model, RCAS
Received: June 18, 2015 Accepted: September 14, 2015 Published: September 24, 2015
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.
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