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.
Highlights
Meningiomas account for approximately one-third of all primary central nervous system tumors and are the most common brain tumor in adults over 35 years of age [1]
We found a correlation of platelet-derived growth factor receptor (PDGFR)-B expression and NF2 inactivation in a cohort of human meningiomas, and we showed that, in mice, Nf2 loss and platelet-derived growth factor (PDGF) overexpression in arachnoid cells induced meningioma malignant transformation, with 40% of Grade II meningiomas
Expression of PDGF receptor-B (PDGFR-B) is correlated with NF2 status in human meningiomas
Summary
Meningiomas account for approximately one-third of all primary central nervous system tumors and are the most common brain tumor in adults over 35 years of age [1]. Most meningiomas are benign and do not recur after complete surgical resection, resulting in prolonged disease free survival and low morbidity. A subset of recurrent and/or histologically aggressive meningiomas (15–25% of tumors, WHO Grade II and III) presents with high morbidity and mortality [2,3,4], and repeated surgeries, radiosurgery/radiotherapy are the only option. Despite recent advances in understanding molecular mechanisms of meningioma development [5, 6], there is no available drug treatment. As in humans, Nf2 and Cdkn2ab loss cooperate to promote progression to histologically aggressive meningiomas [9, 10]
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