Peyre Matthieu, Salaud Céline, Clermont-Taranchon Estelle, Niwa-Kawakita Michiko, Goutagny Stephane, Mawrin Christian, Giovannini Marco, Kalamarides Michel
Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
Université Paris 6 - Pierre et Marie Curie, Paris, France.
Oncotarget. 2015 Oct 20;6(32):32713-22. doi: 10.18632/oncotarget.5296.
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.
血小板源性生长因子-B（PDGF-B）及其受体在脑膜肿瘤发生中的作用尚不清楚。我们通过使用RCAStv-a系统通过血小板衍生生长因子受体（PDGFR）对蛛网膜进行自分泌刺激，研究了PDGF-B在小鼠脑膜瘤发生中的作用。为了特异性靶向脑膜瘤的起源细胞蛛网膜细胞，我们构建了PGDStv-a小鼠（前列腺素D合酶）。在体内，蛛网膜细胞中PDGF-B的强制表达在8个月龄时导致27%的小鼠形成I级脑膜瘤。在体外，PGDS阳性蛛网膜细胞中PDGF-B的过表达导致增殖增加。我们在一组人类脑膜瘤中发现了PDGFR-B表达与神经纤维瘤病2型（NF2）失活之间的相关性，并且我们表明，在小鼠中，蛛网膜细胞中Nf2缺失和PDGF过表达诱导脑膜瘤恶性转化，产生40%的II级脑膜瘤。在这些小鼠中，Cdkn2ab的额外缺失导致恶性脑膜瘤的发生率更高，II级脑膜瘤占60%，III级脑膜瘤占30%。这些数据表明，慢性自分泌PDGF信号可以促进蛛网膜细胞的增殖，并且可能足以诱导脑膜瘤的发生。Nf2和Cdkn2ab的缺失与PDGF-B过表达促进脑膜瘤恶性转化具有协同作用。
