The majority of the intracranial tumors are diffuse-type astrocytomas. These gliomas generally have the common biologic features of 1) micro-infiltrative growth into surrounding brain, and 2) a significant potential for malignant progression to occur over time (i.e. in the residual, infiltrating tumor). The first accounts for the failure of surgery alone and inevitable tumor recurrence, even with gross total resection of the tumor mass. The second accounts for the high rate of increased biologic malignancy in the recurrent tumor. These collectively account for the lack of progress in accurate diagnostic grading and therapy for this class of tumors. The paucity of therapeutic innovations in neuro-oncology reflects the limited understanding of how the migration and invasion of these tumors are controlled, so that the invading tumor cells can be more specifically targeted. Low density lipoprotein receptor-related protein (LRP) is an endocytic receptor involved in the trafficking of a variety of protein/protein complexes that have pathophysiologic relevance in the central nervous system, including urokinase (uPA) and its receptor (uPAR), lipoprotein metabolites, and activated alpha2-macroglobulin. Although the function of LRP in the CNS is not clear, there are abundant data in the literature to indicate that some of its ligands may be involved in key pathophysiologic processes. A variety of cytokines and growth factors, including epidermal growth factor receptor (EGFR) ligands, colony stimulating factor-1 and interferon-gamma, regulate the expression of LRP in both peripheral and central nervous systems. Therefore, changes in LRP expression can alter the levels of its ligands and exert significant biologic effects during cellular responses in the nervous system. Astroglial cells in the human brain express LRP and the level of the receptor is altered in certain reactive states and following neoplastic transformation. Based on our preliminary results in this grant and published data, LRP serves a role as an important endocytic receptor that regulates the level of uPA and its receptor (uPAR), known modulators of migration and invasion, around the microenvironment of astrocytic tumors. We hypothesize that LRP expression regulates the migration and invasion of astrocytic tumor cells. The first goal (Aims 1&2) of this grant is to determine whether the regulation of LRP expression differ between neoplastic (primary astrocytomas; glioblastoma cell lines) and non-neoplastic astrocytes and assess how EGFR or PKC-eta activation alters the expression and endocytic function of LRP. The second goal (Aim 3) is to determine whether overexpression or deficiency of LRP or its ligands (uPA/uPAR) affects astrocytic tumor migration and invasion in vitro and in vivo. Understanding the role of LRP in the migration and invasion astrocytic tumors will provide information on possible specific targets for therapeutic intervention. ? ?
