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Transforming growth factor-beta2 (TGF-beta2) is known to contribute to a malignant course in gliomas partially by inducing a mesenchymal phenotype and by modulating the microenviroment including the extracellular matrix. Matrix metalloproteinase 2 (MMP-2) also correlates with the malignant progression of human gliomas together with cell surface adhesion receptors like integrin alphav beta3. We have described elsewhere that the V0/V1-isoforms of the proteoglycan versican interact with TGF-beta2 and enhance glioma migration. In this study, we aimed to investigate possible interactions of TGF-beta2 with MMP-2 and integrin alphav beta3 that might contribute to glioma migration. Using real-time qPCR to screen for expressional changes in response to TGF-beta2, we showed that TGF-beta2 enhances the expression of MMP-2 and of integrin alphav beta3. Additionally, TGF-beta2 increased the MMP-2 secretion detected by Enzyme Linked-Immuno-Sorbent Assay (ELISA) and the activation of MMP-2 in glioma cells as measured by gelatin zymography. In vitro migration assays demonstrated that the inhibition of MMP-2 activity using a MMP-2 inhibitor suppresses TGF-beta2 stimulated glioma cell-migration. This effect can be enhanced by additional blockade of integrin alphav beta3. We also found that MMP-2 interacts with and cleaves versican V0/V1. Taken together, we outline a new set of interactions involving TGF-beta2, MMP-2, integrin alphav beta3 and the proteoglycan versican which might constitute a crucial network for glioma migration. This molecular cascade may further elucidate the diffuse parenchyma-infiltrating character of glioma invasion and thus be a target for new approaches to anti-tumor therapy.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA