Generation of multiple angiogenesis inhibitors by human pancreatic cancer

A primary inoculum of human pancreatic cancer cells (BxPC-3) has the abilit y to inhibit the growth of a secondary tumor in an in vivo animal model. Su ch ability suggests that the primary tumor is producing inhibitors that act at the site of the secondary tumor. Accordingly we attempted to discover w hich inhibitors are produced by pancreatic cancer cells. We determined that pancreatic cancer cells process angiostatin isoforms from plasminogen. Add itionally, we isolated and characterized an uncleaved "latent" antiangiogen ic antithrombin (aaAT) molecule processed from systemically available AT by pancreatic cancer cells as well as a cleaved form of aaAT processed from s ystemically available AT by pancreatic cancer cells. Human AT, cleaved with human neutrophil elastase, inhibits angiogenesis in the chorioallantoic me mbrane assay. This human aaAT molecule is able to inhibit the growth of pan creatic tumors in immune-compromised mice. Our work represents the first de monstration of multiple angiogenesis inhibitors from a single tumor and sug gests that antiangiogenic therapies may provide an avenue for future treatm ent of pancreatic cancer.