Angiogenesis is necessary for malignant tumor growth and invasion. Current data from other investigators indicate that intact thrombospondin-1 (TSP-1) and peptides derived from the type 1 repeat domain of TSP-1 can inhibit angiogenesis of non-brain microvascular endothelial cells by a mechanism thought to be apoptotic in nature, suggesting the induction of microvascular endothelial cell death is the mechanism by which TSP-1, as well as peptides derived from the type 1 repeat domain, inhibit angiogenesis. Thus, TSP-1 and type 1 repeat peptides will likely inhibit angiogenesis of brain microvascular endothelial cells by inducing apoptosis. This proposal will define by biochemical methods the apoptotic signaling cascade induced by TSP-1 and type 1 repeat peptides in brain microvascular endothelial cells in vitro, confirm and extend these observations using brain microvascular endothelial cells isolated from mice deficient in specific apoptotic signaling molecules, and test the therapeutic efficacy of type 1 repeat peptides in inhibiting angiogenesis and tumor growth in an intracerebral xenograft model of malignant astrocytoma.
