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Generation of multiple angiogenesis inhibitors by human pancreatic cancer
O Kisker1, S Onizuka, J Banyard
1Laboratory of Surgical Research, Children's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Pancreatic cancer cells produce multiple angiogenesis inhibitors, including angiostatin and antiangiogenic antithrombin (aaAT). These molecules inhibit tumor growth, suggesting potential for new antiangiogenic therapies for pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Primary pancreatic tumors can inhibit secondary tumor growth in vivo.
- This suggests the production of tumor-derived inhibitory molecules.
Purpose of the Study:
- To identify specific inhibitors produced by pancreatic cancer cells.
- To investigate the antiangiogenic potential of these molecules.
Main Methods:
- Analysis of pancreatic cancer cell lines (BxPC-3) for inhibitor production.
- Processing and characterization of angiostatin isoforms and antiangiogenic antithrombin (aaAT).
- In vitro angiogenesis assays (chorioallantoic membrane) and in vivo tumor growth inhibition studies in immune-compromised mice.
Main Results:
- Pancreatic cancer cells process angiostatin isoforms from plasminogen.
- Pancreatic cancer cells produce both latent and cleaved forms of antiangiogenic antithrombin (aaAT) from systemic antithrombin.
- Human aaAT inhibits angiogenesis and pancreatic tumor growth in vivo.
Conclusions:
- Pancreatic tumors can generate multiple endogenous angiogenesis inhibitors.
- This discovery supports the development of antiangiogenic therapies for pancreatic cancer treatment.