MMP-2 mediates mesenchymal stem cell tropism towards medulloblastoma tumors

Abstract

Matrix metalloproteinases (MMPs) are a family of proteinases known to have a role in cell migration. In the present study, we evaluated the role of MMP-2 on tropism of human umbilical cord blood-derived stem cells (hUCBSCs) in a human medulloblastoma tumor model. Consequences of MMP-2 inhibition on stem cell tropism towards medulloblastoma were studied in terms of stem cell migration by using cell culture inserts, transwell chamber assay, western blotting for MMP-2 and migratory molecules, and immunohistochemistry. Conditioned medium from Daoy/D283 cells infected with adenoviral vector encoding MMP-2 small interfering RNA (siRNA) (Ad-MMP-2 si)-reduced stem cell migration as compared with conditioned medium from mock and scrambled vector (Ad-SV) infected cells. In addition, MMP-2 inhibition in the tumor cells decreased the expression of stromal cell-derived factor 1 (SDF1) in the tumor-conditioned medium, which results in impaired SDF1/CXCR4 signaling leading to decreased stem cell tropism towards the tumor cells. We further show that MMP-2 inhibition in the tumor cells repressed stem cell tropism towards medulloblastoma tumors in vivo. In summary, we conclude that hUCBSCs can integrate into human medulloblastoma after local delivery and that MMP-2 expression by the tumor cells mediates this response through the SDF1/CXCR4 axis.