Malignant gliomas account for the majority of primary brain tumors in the adult and for a significant number of pediatric brain tumors. Most of these tumors are astrocytomas, of which glioblastomas account for the majority in the adult. Astrocytomas possess the ability to invade and infiltrate brain parenchyma, resulting in tumors which are difficult to remove entirely by surgical and other therapeutic means. This proposal focuses on the identification of extracellular matrix (ECM) molecules which may inhibit the ability of these tumors to infiltrate the brain parenchyma in vivo. Type IV collagen, fibronectin and laminin are major components of the ECM in peripheral organs but are absent in the adult CNS except around blood vessels and the brain covering (leptomeninges). These structures are not being infiltrated by astrocytoma cells, and I hypothesize that one or more of these ECM proteins may have an inhibitory effect upon astrocytoma cell infiltration in vivo. Rat and mouse tumor cell lines of fibroblastic and epithelial origins from peripheral (outside of the central nervous system) organs will be screened for their ability to secrete type IV collagen, fibronectin and/or laminin. These cells will be co-injected together with retrovirally-marked infiltrative rat glioblastoma cells into the rat brain, and the effect of the ECM proteins on the growth behavior of the labeled glioblastoma cells in the mixed tumors will be analyzed by histochemical and immunohistochemical means. The long term goal of the proposal is to characterize tumor infiltration-inhibitory molecules and to develop the proper mechanisms so that these proteins, or sub-fragment derived from them, could be delivered intracerebrally in brain tumor patients for therapeutic purposes.
