Thrombospondin-1 (TSP-1), an endogenous angiogenisis inhibitor, is normally secreted by many cell types. Tumors of various origins, including glioblastomas, have been found to down-regulate thrombospondin-1 (TSP-1) expression. We have previously shown that overexpression of TSP-1 in human glioblastoma cells reduces their tumorigenicity in immunocompromised mice, apparently due to inhibition of angiogenesis. We propose to extend our tumorigenicity studies by determining whether induced expression of TSP-1 in a pre-existing brain tumor will result in arrest or reversal of tumor growth in subcutaneous and intracranial glioma models. Additionally, we plan to investigate if mini-TSP-1 proteins containing solely type 1 repeats will have anti-angiogenic activities comparable to full length TSP-1. We will ultimately use neural progenitor cells as a therapeutic tool to deliver TSP-1 or mini-TSP-1 in an intracranial glioma model. With this approach steady and efficacious levels of TSP-1 or mini-TSP-1 will be ideally achievable at the tumor sites. Experimental success in this treatment modality will be readily adaptable to a clinical situation, and could lead to new and highly effective treatment for glioblastomas and other types of cancer. ? ?
|Kaur, Balveen; Tan, Chalet; Brat, Daniel J et al. (2004) Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 70:229-43|