Glioblastoma multiforme (GBM) is the most malignant and common brain tumor. The diffusively infiltrative nature of GBMs is one of the major causes of mortality in patients afflicted with this form of cancer. Studies to assess the invasiveness of glioma cells in vitro have demonstrated a strong correlation between glioma invasion and high levels of matrix metalloproteinase-9 (MMP-9) expression; in this regard, selective inhibition of MMP-9 represents an important therapeutic target for treatment of GBMs. Interferons (IFNs) are multi-functional cytokines that have anti-viral, anti-proliferative, anti-angiogenic and immunomodulatory effects. We have made the novel observation that IFN-gamma and IFN-beta potently inhibit MMP-9 gene expression in human glioma cells. We hypothesize that IFNs will have an inhibitory influence on glioma cells, leading to the arrest of tumor cell invasion and angiogenesis via the suppression of MMP-9 expression. We will identify, for the first time, the molecular mechanisms underlying the in vitro inhibitory effects of IFN-gamma and IFN-beta, and investigate the involvement of two transcription factors, STAT-1alpha and CIITA, in this response (Specific Aims #1 and #2). These data will further our understanding of the regulatory mechanisms of MMP-9 gene transcription and identify important therapeutic targets to abrogate MMP-9 expression. In vivo studies will follow to validate the effectiveness of IFN suppression of MMP-9. The efficacy of IFN-gamma and IFN-beta gene therapy on the growth, invasion and angiogenic properties of human glioma cells transplanted into the brains of immunocompromised mice will be examined (Specific Aim #3). Lastly, we have the unique opportunity to evaluate the effectiveness of IFN-beta gene transfer in patients with GBMs (Specific Aim #4). The combination of in vitro basic science experiments and translational in vivo studies will lead to a comprehensive understanding of the role of MMP-9 in glioma cell biology, and the potential of IFNs to ameliorate the detrimental effects of MMPs.
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