Role of MMP9/iNOS/COX-2 in Macrophages/Microglia-Activated Glioma Invasion

Malignant brain tumors are among the most fatal cancers. Even with aggressive surgical intervention with irradiation and chemotherapy, few patients with malignant glioma survive longer than 2 years from the time of diagnosis. Diffuse astrocytic gliomas are the largest group of brain tumors including fibrillary and gemistocytic astrocytoma, anaplastic astrocytoma (grade III), and the most malignant glioblastoma (grade IV). Extensive invasion into non-neoplastic brain reduces the possibility to complete surgical resection and is associated with a poor diagnosis. Recent studies indicated the contribution of microenvironment to the metastasis of several tumors such as breast carcinoma, colon carcinoma, and lung cancer, and a close relationship between macrophages activation and tumor metastasis has been identified. A number of nonmalignant cells such a lymphocytes, macrophages and microglia comprise the glioma microenvironment to influence the tumor growth and limit the efficacy of therapy. Recent studies indicated the contribution of microenvironment to the metastasis of several tumors such as breast carcinoma, colon carcinoma, and lung cancer, and a close relationship between macrophages activation and tumor metastasis has been identified. A number of nonmalignant cells such as lymphocytes, macrophages and microglia comprise the glioma microenvironment to influence the tumor growth and limit the efficacy of therapy. However, the contribution of microenvironmental cells on glioma invasion is still unclear completely. Our previous study showed that LPS treatment was able to induce C6 glioma cells invasion. We further found that inflammatory inducers LPS、LTA、PGN treatment significantly induced MMP9 enzyme activity 、iNOS/NO and COX-2/PGE2 production in microglia/macrophages. Similar data derived from condition medium from glioma cells-induced MMP9 enzyme activity、iNOS/NO and COX-2/PGE2 production have been obtained. Therefore, in the present project, we will investigate the contribution of microglia/macrophages activation by inflammatory stimulus and glioma condition medium on the invasion of glioma in vitro and in vivo. Contribution of inflammation or glioma activated macrophages/microglia on glioma invasion will be elucidated. This is a three-year project, and specific aims and hypothesis are described below. Specific aim I: Investigating the activation mechanism of microglia/macrophages-induced MMP9/iNOS/COX-2 elicited by inflammatory inducers (LPS、LTA、PGN)與conditional medium (CM) from glioma cells Hypothesis I: Inflammatory inducers and CM from glima cells induce MMP9/iNOS/COX-2 activation in macrophages/microglia Specific aim II: Investigating the MMP9/iNOS/COX-2 from activated macrophages/microglia on glioma invasion in vitro Hypothesis II: MMP9/iNOS/COX-2 induced by activated macrophages/microglia promotes glioma invasion in vitro Specific aim III: Investigating the roles of macrophages/microglia activation on glioma invasion in vivo Hypothesis III: Macrophages/microglia activation stimulates glioma invasion via MMP9/iNOS/COX-2 production in vivo