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Professor, Neuroscience Professor, Sol Sherry Thrombosis Research Center Location: Room 754 MERB Telephone: 215-707-6451 Fax: 215-707-4888 Email: gpt@temple.edu
Department of NeuroscienceSol Sherry Thrombosis Research Center
Angiogenesis, metastasis, tumor progression, tumor markers, experimental cancer therapeutics.
In 1987, our laboratory first showed that thrombospondin -1 (TSP-1), a platelet protein, functioned as a cell and platelet adhesive protein and that TSP-1 could promote metastasis formation in a murine model of experimental metastasis. Since then we have identified structural domains within the TSP-1 molecule and a new TSP-1 receptor that may mediate cell-cell and cell-substratum interactions operative during the metastatic cascade and the process of angiogenesis. We found that a number of peptides homologous to CSVTCG promoted the adhesion of a variety of normal and tumor cells and inhibited platelet aggregation and tumor cell metastasis, whereas control peptides had no effect. Our results further demonstrated that these peptides inhibited tumor lung metastases and angiogenesis presumably by competing with endogenous TSP-1 for TSP-1 tumor cell receptor sites. This conclusion was further supported by the observation that anti-CSTSCG antibody, which specifically recognized TSP-1, inhibited TSP-1-dependent cell adhesion, platelet aggregation, and tumor cell metastasis, whereas control IgG had no effect. These results suggest that CSVTCG and CSTSCG present in the type I repeat sequences of TSP-1 function in the adhesive interactions of TSP-1 that mediate platelet aggregation, angiogenesis and tumor cell metastasis.
The TSP-1 receptor specific for the CSVTCG residues in the type 1 repeats of TSP-1 was isolated from lung carcinoma by CSVTCG-Sepharose chromatography. Anti-receptor IgG and inhibited lung carcinoma cell spreading and adhesion and platelet adhesion on TSP-1 but not on fibronectin and laminin. Anti-CSVTCG receptor antibody blocked breast cancer invasion in vitro and metastasis and tumor progression in an in vivo athymic model of breast cancer progression. These data as well as immunohistochemical studies showing that this receptor highly over-exepressed in breast carcinoma and its neovasculature as well as many other tumors, including lung, melanoma, ovarian, prostate, pancreatic, colon, gastric, and hepatocelluar carcinoma and that this receptor is predictive of poor patient outcome in squamous carcinoma of the head and neck strongly support the conclusion that both TSP-1 and its receptor mediate cancer progression.
The receptor has recently been cloned and expressed as a soluble protein in bacteria. Recombinant protein, referred to as angiocidin, specifically inhibited endothelial adhesion, tube formation and viability, while having no effect on a variety of cells including fibroblasts, smooth muscle cells, and tumor cells. Angiocidin localized to the vasculature and inhibited Lewis Lung carcinoma and B16F10 melanoma growth in mice by more than 95%. Similarly, a monoclonal receptor antibody inhibited more than 50% tumor growth. Therefore, angiocidin may be new target for the development of an anti-angiogenic agent for the treatment of cancer.
Based on these results, we believe that CSVTCG peptides and the CSVTCG specific TSP-1 receptor (angiocidin) are targets for the development of cancer therapeutics, angiogenesis inhibitors and imaging agents as well as anti-thrombotics. Preclinical studies are now underway in preparation for the use of angiocidin, anti-angiocidin antibodies and the CSVTCG peptides for the treatment of cancer in man. Finally our laboratory is searching for new molecules and new mechanisms that can be targeted for development of cancer therapeutics and diagnostics. In collaboration with Dr. Mahesh Sharma, we have identified annexin II as a potential receptor mediating angiogenesis and tumor progression. We have developed a monoclonal annexin II antibody that reduces tumor growth by more than 50%. This antibody may also find utility as a diagnostic tool for the detection of annexin II in sera and solid tumors.
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George P. Tuszynski, PhD