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 metastases (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 by gene transfer of a cDNA coding for mouse angiostatin into murine T241 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo. Implantation of stable clones expressing mouse angiostatin in C57Bl6/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 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 time shows the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angiogenesis. Our data may also provide a novel approach for cancer therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor.
Cao
Y
Y
Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77, Stockholm, Sweden. yihai.cao@mtc.ki.se
O'Reilly
M S
MS
Marshall
B
B
Flynn
E
E
Ji
R W
RW
Folkman
J
J
D043168:Angiostatins; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002999:Clone Cells; D003001:Cloning, Molecular; D003315:Cornea; D018076:DNA, Complementary / Q000235:genetics; D005354:Fibrosarcoma / Q000235:genetics*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*; D010958:Plasminogen / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation
D018076:DNA, Complementary; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen