Matrix Metalloproteinase 1 Is Necessary for the Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Human Glioma

Abstract

Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non–tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis. Stem Cells 2009;27:1366–1375

Gene expression profiling identifies sST2 as an effector of ErbB2-driven breast carcinoma cell motility, associated with metastasis

“…Moreover, sST2 is secreted by metastatic breast cancer cells and found at high levels in the serum of patients with metastatic tumors. Among the genes most highly regulated by ErbB2, we found the MMPs MMP1 and MMP10 which have been involved previously in cell migration (Dufour et al, 2008;Ho et al, 2009). But MMP1 and MMP10 did not contribute to cell motility in our experimental system.…”

Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation

“…TGF-a and EGFR overexpression in CP 13 is consistent with the observed upregulation of MMP-1 in CP in our study. The known involvement of MMP-1 in the migration of human mesenchymal stem cells 27 also supports a role for MMP-1 in PSC migration. As MMP-1 has a crucial role in tumor cell invasion, 24,28 and TGF-a is reportedly upregulated in several pancreatic cancer cell lines, 15 MMP-1 upregulation in TGF-a-activated PSCs may be important for pancreatic Figure 9 The partial colocalization of transforming growth factor (TGF)-b1 and TGF-a in the pancreatic tissues of a chronic pancreas sample.…”

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

“…Increased levels of inflammatory cytokines enhance in autocrine manner expression of proteases such as MMP-2, -9 and -14 in MSCs that promote MSC motility towards the tumour (Ries et al, 2007). Ho et al (2009) showed that MMP-1 is crucial for MSC migration toward glioma in vivo, as well as in vitro. MMP-1 cleaves G-proteincoupled receptor PAR1 on MSC surface, triggering intracellular signalling, which promotes MSC glioma tropism.…”