Arrested migration fosters apoptosis of glioma cells

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DESCRIPTION (provided by applicant): The malignant behavior of glioma cells involves uncontrolled proliferation, parenchymal invasion, and diminished accessibility or activity of apoptosis pathways. Genomic profiling of neoplastic glial cells gives insight into the underlying basis for the dysregulation prompting each of these behaviors. Recently, functional associations linking accelerated migration with suppressed proliferation, and induced motility with diminished apoptosis argue for more detailed study of ways in which these distinct features of the malignant phenotype impact one another. The central hypothesis of this project is that arrested migration fosters apoptosis of malignant gloom cells. The Specific Aims are: 1) Assess the quantitative relationship between rate of migration and susceptibility to cell death. The migration rate of gloom cells will modulated by adherence to migration stimulating purified ECM proteins, forced over expression or down regulation of migration inducing proteins and pharmacological or immunological manipulation of cell surface receptor or signal transduction pathways modulating migration. Effects on apoptosis induction by clinically useful agents will be assessed. Multiple cell lines and primary glioblastoma explants will be used to determine if this is a universal phenomenon among glioma cells. 2) Test whether arrested migration of glioma cells leads to facilitated activation of cell death in vivo. Results from Specific Aim 1 will be used to identify targets to manipulate that will facilitate induction of cell death. Xenograft models of glioma tumors will be used to assess effects of migration suppressors on induction of cell death in vivo by cytotoxic agents. In its description of Priorities and Plans for the NINDS (published most recently in August, 1999), the Neural Environment cluster states that "A goal is to sequence all genes activated when this tumor (glioma) arises in order to understand what causes uncontrolled tumor cell proliferation and invasion of surrounding brain tissue." The need for improved discovery of mechanisms of glioma invasion was reiterated in recent Progress Review Group report on Brain Tumors, co-sponsored by the NCI and the NINDS. Consistent requirements of the R21 Program Guidelines, this project outlines development of novel technologies focused on ways to discover and exploit anti-migratory or anti-invasive strategies as potentiating interventions for improving cytotoxic therapy against glial cell tumors.