Primary tumors of the central nervous system, gliomas, are notoriously difficult to control, due in large measure to their highly invasive behavior. The ability of cells to migrate through tissue depends, in part, on the composition of the tissues extracellular matrix (ECM). Understanding the molecular composition of the extracellular environment of brain tumors is one approach to developing methods to prevent tumor invasion. BEHAB/brevican, a recently identified brain-specific ECM protein, is markedly upregulated in human glioma and in experimental models of glioma. In human glioma BEHAB/brevican expression is 700 percent over that in the normal adult human brain and expression is not detected in any non-glial derived tumor, even when these tumors grow within the brain. Our work during the previous funding period has provided evidence that BEHAB/brevican plays a role in glioma invasion. The experiments proposed here will test this hypothesis and, in addition, will test the possibility that BEHAB/brevican may provide a novel therapeutic target for glioma. In experimental glioma cel models, BEHAB/brevican expression is induced by a brain-specific factor. The first specific aim of this application is to characterize the mechanism of BEHAB/brevican induction and to identify potential inducing factors. Several converging lines of evidence suggest that proteolytic processing is required for BEHAB/brevican function in glioma invasion. The second specific aim of this application is to characterize BEHAB/brevican Droteolytic cleava2e in glioma. Slowing or preventing glioma cell motility could increase the efficacy of regional therapies; the third specific aim of this application is to determine whether inhibitors of BEHAB/brevican cleavage can slow tumor invasion and, therefore, might provide a new therapeutic avenue foi glioma. Our work has led to the hypothesis that production, cleavage, and turnover of BEHAB/brevican together modulate the ECM and can regulate cell motility. Our final specific aim is to test a role for BEHAB/brevican turnover in glioma invasion. Our long-term goal is to determine if functional reduction or elimination of BEHAB could slow the progression of primary brain tumor.
