title: Plasminogen activators are involved in angiostatin generation in vivo in benign and malignant ovarian tumor cyst fluids.
abstract: In many tumor types, angiogenesis is the net result of pro- and anti-angiogenic mediators and correlated with metabolic activity, growth, and degree of malignancy. One of the first discovered anti-angiogenic compounds is angiostatin, a proteolytic fragment of plasminogen. The requirements for in vivo angiostatin generation have not yet been determined. We investigated the levels of plasminogen and angiostatin by western blotting and of components of the plasminogen activator complex by ELISA in cyst fluid derived from benign and malignant ovarian tumors. Fluid samples from functional ovarian follicles, dermoid cysts and endometriotic lesions were evaluated separately. When no or minimal amounts of plasminogen were present in the cyst fluids, angiostatin was generally absent as well, irrespective of plasminogen activator concentrations. When plasminogen was present, the degree of conversion of plasminogen to angiostatin was significantly correlated with the level of uPA, and, to a lesser extent, to the tPA level. However, angiostatin was also found in a number of cyst fluid samples with minimal or no plasminogen activators, suggesting the involvement of other angiostatin generating proteases in these samples. Conversely, no angiostatin was observed in a number of cyst fluid samples containing both plasminogen and plasminogen activators. The presence of an inhibitor of the enzymatic activity of uPA and/or tPA, like PAI-1, may explain this finding. Our data show that plasminogen activators are clearly involved in in vivo angiostatin formation in ovarian cysts. Most likely, however, other proteases, as well as inhibitors of plasminogen activators, are involved as well.
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A A G
authors.initials: AA
authors.lastname: van Tilborg
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Geurts-Moespot
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A M M
authors.initials: AM
authors.lastname: Wetzels
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R M W
authors.initials: RM
authors.lastname: de Waal
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: Westphal
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: L F A G
authors.initials: LF
authors.lastname: Massuger
mesh_terms: D043168:Angiostatins / Q000096:biosynthesis*; D020420:Cyst Fluid; D003884:Dermoid Cyst / Q000473:pathology; D004715:Endometriosis / Q000473:pathology; D005260:Female; D006801:Humans; D010048:Ovarian Cysts / Q000473:pathology*; D006080:Ovarian Follicle / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology*; D010958:Plasminogen / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D043168:Angiostatins; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator