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Generation of Multiple Angiogenesis Inhibitors by Human Pancreatic Cancer¹

Laboratory of Surgical Research, Children’s Hospital, Boston, Massachusetts 02115 [O. K., S. O., J. B., C. M. Be., E. G. A., C. M. Ba., J. F., S. R. P-S.]; University Hospital Marburg, Department of General Surgery, Philipps University, Marburg, Germany [O. K.]; Department of Surgery II, Nagasaki University, Nagasaki Japan [S. O.]; Department of Biological Chemistry, University Michigan Medical School, Ann Arbor, Michigan 48109 [T. K.]; University Hospital Benjamin Franklin, Department of Gynecology and Obstetrics, Free University Berlin, Berlin, Germany [C. M. Be.]; University Hospital Hamburg, Department of Hepato-Biliary Surgery, University of Hamburg, Hamburg, Germany [E. G. A.]; Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030 [M. S. O.]; Departments of Surgery and Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 [J. F.]; and Attenuon LLC, San Diego, California 92121 [S. R. P-S.]

A primary inoculum of human pancreatic cancer cells (BxPC-3) has the ability to inhibit the growth of a secondary tumor in an in vivo animal model. Such ability suggests that the primary tumor is producing inhibitors that act at the site of the secondary tumor. Accordingly we attempted to discover which inhibitors are produced by pancreatic cancer cells. We determined that pancreatic cancer cells process angiostatin isoforms from plasminogen. Additionally, we isolated and characterized an uncleaved "latent" antiangiogenic antithrombin (aaAT) molecule processed from systemically available AT by pancreatic cancer cells as well as a cleaved form of aaAT processed from systemically available AT by pancreatic cancer cells. Human AT, cleaved with human neutrophil elastase, inhibits angiogenesis in the chorioallantoic membrane assay. This human aaAT molecule is able to inhibit the growth of pancreatic tumors in immune-compromised mice. Our work represents the first demonstration of multiple angiogenesis inhibitors from a single tumor and suggests that antiangiogenic therapies may provide an avenue for future treatment of pancreatic cancer.

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