The long-term goal of our research is to improve therapy for patients with invasive gliomas through a better understanding of the mechanisms by which these tumors invade normal brain tissues. Invasion of glioma cells into adjacent brain structures occurs through the activation of multigenic programs including matrix metalloproteases (MMPs) that degrade extracellular matrix (ECM) at tumor invasive fronts to overcome the ECM barrier. Recently, we have demonstrated that angiopoietin-2 (Ang2), a known angiogenic factor, induces glioma invasion through the activation of MMP-2 and membrane type-1 (MT1)-MMP. We analyzed a large number of primary human glioma biopsies and found that Ang2, MMP-2 and MT1-MMP are co-overexpressed in the invasive areas, but not in the central regions, of these tumors. Consonantly, high expression of Ang2, MMP-2 and MT1-MMP are also evident in the actively invading regions of human U87MG Ang2-expressing glioma xenografts. Stable expression of Ang2 or exposure of glioma cells to exogenous Ang2 also caused an up-regulation of MMP-2 and MT1-MMP and acquisition of increased invasiveness in vitro. We have started to investigate the mechanisms by which Ang2 stimulates glioma invasion. We found that Ang2 stimulates the secretion of MMP-2 by interacting with beta1and (alphavbeta3 integrins leading to activation of the focal adhesion kinase (FAK)-mediated pathway. Ang2 also stimulates the expression of MT1-MMP by interacting with beta1 and alphav1beta3 leading to activation of the nuclear factor kappaB (NF-kappaB)-mediated pathway. In addition, transcriptional profiles of U87MG/Ang2 glioma cells analyzed by DNA arrays revealed that multiple sets of genes regulated by Ang2 are also involved in tumor invasion by various types of human cancers. The goal of this revised application is to further characterize Ang2-induced invasion, to determine the mechanisms of Ang2-induced invasiveness, and establish therapeutic approaches for inhibiting Ang2-induced glioma invasion. To achieve our goal, we have developed the following four aims: 1) characterize Ang2-induced glioma invasion, 2). determine the mechanisms by which Ang2 stimulates MMP-2 secretion and glioma cell invasion via the integrin/FAK mediated pathway, 3). determine the mechanisms by which Ang2 stimulates MTI-MMP expression and glioma cell invasion via the integrin NF-KappaB-mediated pathway 4). explore therapeutic approaches for inhibiting Ang2-stimulated glioma invasion. The proposed studies will aid our understanding of the molecular mechanisms of glioma invasion. This application will enable us to decipher the multigenic programs activated in glioma invasion and significantly improve our current understanding of the mechanisms underlying the invasive phenotype of glioma cells. These studies could establish Ang2 and its effectors as potential therapeutic targets leading to the development of new anti-invasion strategies for glioma treatments.
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