EXPRESSION OF ANGIOSTATIN CDNA IN A MURINE FIBROSARCOMA SUPPRESSES PRIMARY TUMOR-GROWTH AND PRODUCES LONG-TERM DORMANCY OF METASTASES

Tumor growth and metastasis are angiogenesis dependent, Previously, we reported that angiostatin, a potent angiogenesis inhibitor, produced by a primary Lewis lung carcinoma suppressed its growth of lung metast ases (O'Reilly, M.S., L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, M. Moses, W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman. 1994. Cell. 79 :315-328), Now we show that a shift of balance of tumor angiogenesis b y gene transfer of a cDNA coding for mouse angiostatin into murine T24 1 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo, Implantation of stable clones expressing mouse angiostatin in C 57B16/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in similar t o 70% Of mice remain in a microscopic dormant and avascular state for the duration of the experiments, e.g., 2-5 mo, The tumor cells in the dormant micrometastases exhibit a high rate of apoptosis balanced by a high proliferation rate, Our study, to our knowledge, for the first t ime shows the diminished growth of lung metastases after removal of th e primary tumor, suggesting that metastases are self-inhibitory by hal ting angiogenesis. Our data may also provide a novel approach for canc er therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor.