Role of MMP16 in Malignant and Invasive Meningiomas

Abstract

Skull base meningiomas are typically managed by surgical resection. However, in the instances of malignant, hyperostotic, or bone invasive skull base meningiomas, complete surgical resection is not possible and management of this subpopulation of meningiomas becomes challenging. We aimed to identify novel signaling molecules mediating brain and bone invasion of meningiomas to be able to identify targeted therapeutics. We performed microarray analysis on malignant versus non-malignant meningiomas, plus bone-invasive and non-invasive meningiomas, and identified more than 200 differentially expressed genes. For the purposes of this study, we focused on the role of Membrane Type III-Matrix Metalloproteinase (MT3-MMP) or MMP16 in bone-invasive and malignant meningiomas. We confirmed elevated expression of MMP16 in malignant and bone-invasive meningiomas compared with non-malignant or non-invasive tumors using real-time PCR analysis. We next studied the in vitro and in vivo characteristics of meningioma cell lines transfected to over-express and under-express MMP16. Knock-down of MMP16 showed statistically significant reduced invasion in vitro using basement membrane, matrigel, and wound-healing assays. Furthermore, knock-down of MMP16, using zymography, demonstrated an alteration in activity of other MMPs, including MMP2 and MMP9. Knock-down of MMP16 reduced tumor progression, as confirmed by volumetric assessment of serial MRI images of xenograft meningioma tumors. To prove that MMP16 contributes to invasive phenotype of meningiomas, we reintroduced MMP16 in meningioma lines with parental low MMP16 or knock-down MMP16 cells and found an increase in growth rate and invasion.