The goal of this application is to test the hypothesis that a circulating inhibitor of vascular endothelial cell growth released by primary tumors inhibits the growth of metastases. The phenomenon of suppression of tumor growth by tumor mass is well-known, but a molecular mechanism has not been elucidated. Our preliminary data show that: (i) Primary mouse tumors inhibit growth of lung metastases; (ii) Removal of the tumor increases the number of visible metastases by 12-fold and the maximum size by 1000-fold; (iii) The suppression of metastatic growth appears to be due to inhibition of neovascularization and not to a direct inhibitory effect on the tumor cells; (iv) A specific inhibitor of endothelial proliferation has been isolated from serum and urine of tumor-bearing mice but not from mice with tumors removed. Tumor cells and other cell types are not inhibited. (v) The inhibitor has been purified from mouse urine as a 38 kD protein with an amino acid sequence homologous to an internal fragment of plasminogen, having an N-terminus at amino acid 98 and a predicted carboxy-terminus at amino acid 440, and named """"""""angiostatin."""""""" Full length plasminogen itself has no endothelial inhibitory activity. Human angiostatin co-purifies with murine angiostatin and the human cDNA has been cloned. Human angiostatin potently inhibits angiogenesis within lung metastases and growth of metastases.
Our Specific Aims are to: (1) Produce sufficient quantities of angiostatin; (2) Determine its therapeutic activity. (3) Initiate structure-activity studies of angiostatin by transfection of its cDNA and deletion mutants. (4) Identify and isolate the membrane receptor for angiostatin on vascular endothelial cells. Significance: These studies may provide: (i) A mechanism for suppression of metastasis by tumor mass; (ii) Additional direct evidence that tumor growth is angiogenesis-dependent; (iii) A novel method of discovering endogenous angiogenesis inhibitors; (iv) A possible new concept of tumor dormancy; (v) A potential new diagnostic and therapeutic approach in cancer patients.
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