Malignant brain tumors represent one of the most refractory cancers to therapy and remain incurable. Gliomas represent the most common type of brain tumors and occur in various grades, with the patient's prognosis inversely proportional to the grade. Our laboratory has been active in the study of proteases and their inhibitors in the biology of brain tumors, and data generated so far have indicated that changes in these molecules are correlated with the changes in the grade of the tumors. For instance, glioblastomas, when compared with low-grade gliomas, have shown significantly higher PAI-1, uPA, uPA receptor, and 92-kDa collagenase levels, whereas low-grade gliomas have higher tPA and TIMP levels. It is, therefore, our hypothesis that the malignant phenotype and the invasive behaviors of the various grades of gliomas are determined, in part, by the activity of specific proteases and their inhibitors. Our second hypothesis is that regulation of angiogenic growth factors in gliomas induces changes in the production of proteases and their inhibitors, thereby modulating the invasive nature of the tumor. Finally, our third hypothesis postulates that the genetic alterations involved in oncogenesis of gliomas, regulate, at least in part, the invasive phenotype of the tumors. In this proposal we will quantitate the invasiveness of human gliomas with in vivo MRI measurements and in vitro Matrigel and spheroid models. Key proteolytic enzymes (uPA, 92-kd collagenase, cathepsin B) and their inhibitors (PAI-1, TIMP-1 and CPI) along with uPA-receptor will be measured in the human samples and in their primary cultures. The results of these studies will strengthen our understanding of the role of these proteases in the biologic behavior of the tumors and confirm their significance as prognostic markers. Other studies to be carried have been designed to modulate the invasiveness of the glioma cells using chemicals, antibodies, and oligonucleotides in order to better define the respective role that the various enzymes play in the invasiveness process and to prepare for the clinical protocols described in Project 1. The invasiveness of tumor cells is closely related to angiogenesis, which in itself is an expression of endothelial cell invasiveness. For this reason, and in relation to Project 2, we will determine the modulating effect of VEGF and FGF oligonucleotides on the invasiveness of GBM cell lines. Finally, similar studies will be performed on the cell lines that have been re-engineered with a complete copy of chromosomes 4 or 10 to determine their invasive capacity and their production of proteases and inhibitors. Together these studies should provide important insights into the roles of proteases and their inhibitors in the progression of human gliomas, with the hope of providing new prognostic markers and new therapeutic avenues.
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