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Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis
S Gately1, P Twardowski, M S Stack
1Division of Hematology/Oncology, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Abstract:
Angiostatin is an inhibitor of angiogenesis and metastatic growth that is found in tumor-bearing animals and can be generated in vitro by the proteolytic cleavage of plasminogen. The mechanism by which angiostatin is produced in vivo has not been defined. We now demonstrate that human prostate carcinoma cell lines (PC-3, DU-145, and LN-CaP) express enzymatic activity that can generate bioactive angiostatin from purified human plasminogen or plasmin. Affinity purified PC-3-derived angiostatin inhibited human endothelial cell proliferation, basic fibroblast growth factor-induced migration, endothelial cell tube formation, and basic fibroblast growth factor-induced corneal angiogenesis. Studies with proteinase inhibitors demonstrated that a serine proteinase is necessary for angiostatin generation. These data indicate that bioactive angiostatin can be generated directly by human prostate cancer cells and that serine proteinase activity is necessary for angiostatin generation.
Insights
Human prostate cancer cells can generate angiostatin, a protein that inhibits tumor growth and metastasis. This process requires specific serine proteinase activity, offering new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Angiostatin is a known inhibitor of angiogenesis and metastatic growth.
- Its in vivo generation mechanism, particularly by cancer cells, remains undefined.
- Plasminogen cleavage is a known in vitro method for angiostatin production.
Purpose of the Study:
- To investigate the mechanism of angiostatin generation by human prostate carcinoma cell lines.
- To determine if prostate cancer cells possess enzymatic activity to produce bioactive angiostatin.
- To identify the enzymatic requirements for in vivo angiostatin generation.
Main Methods:
- Human prostate carcinoma cell lines (PC-3, DU-145, LN-CaP) were used.
- Enzymatic activity was assessed using purified human plasminogen and plasmin.
- Affinity purification of PC-3-derived angiostatin was performed.
- In vitro assays measured inhibition of endothelial cell proliferation, migration, tube formation, and angiogenesis.
- Proteinase inhibitors were employed to identify necessary enzymes.
Main Results:
- Human prostate carcinoma cell lines demonstrated enzymatic activity to generate bioactive angiostatin from plasminogen/plasmin.
- PC-3-derived angiostatin exhibited anti-angiogenic and anti-metastatic properties in vitro and in vivo models.
- Serine proteinase activity was identified as essential for angiostatin generation by these cells.
Conclusions:
- Human prostate cancer cells can directly generate bioactive angiostatin.
- Serine proteinase activity is crucial for this cancer-cell-mediated angiostatin production.
- These findings suggest a novel pathway for endogenous angiostatin generation with therapeutic implications.