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Plasminogen Activator Profiles in Neoplastic Tissues of the Human Colon

Departments of Gastroenterology and Hepatology [P. A. F. de B., G. G., H. W. V., C. B. H. W. L.] and Pathology [H. F. v. d. I.], University Hospital, and Gaubius Institute TNO [J. H. V., G. D.], Leiden, The Netherlands

Plasminogen activator (PA) activity, in particular urokinase (u-PA), has been shown to be markedly increased in adenocarcinomas of the colon. Adenomatous polyps were found to be intermediate in their PA activity to normal mucosa and adenocarcinomas. In the present study we evaluated the PA profile in relation to malignancy parameters of the adenomas.

Forty-eight adenomatous polyps, obtained by endoscopic polypectomy, were scored according to size, histological type, and grade of dysplasia. In extracts, tissue-type PA (t-PA) and u-PA were determined using a spectrophotometric enzyme assay, antigen assays, and a bioimmunoassay for u-PA. Twenty-five paired samples of normal mucosa and adenocarcinoma were used as controls. Additionally, four hyperplastic polyps were studied by the same methods. The presence of complexes of PA with PA inhibitors was assessed by zymography.

A 10-fold increase of u-PA antigen in carcinomas was found as compared to normal tissue. An increase was also noted in u-PA activity, although its extent was less, due to the fact that 74% of u-PA was in the inactive proenzyme form. Adenomatous polyps contained PA activities and antigens intermediate to those of normal mucosa and carcinomas, in accordance with the view that they are precursors in the development of colorectal cancer. Within the adenoma group, no relation was found between PA profile changes and histological type or polyp size. Surprisingly, in a group of four hyperplastic polyps, similar profiles of PA were found as in adenomas. When the u-PA/t-PA antigen ratio was taken as a parameter of developing malignancy, two discrete increases were seen during the adenoma-carcinoma sequence, the first at adenoma formation and the second accompanying the start of invasive growth in polyps with severe dysplasia.

Zymography showed that only t-PA was present in complex with specific PA inhibitors, explaining how the decrease of t-PA activity in adenomas and carcinomas could be stronger than the parallel decrease of t-PA antigen, when these were compared with normal mucosa, which contained hardly any complexes.

¹ To whom requests for reprints should be addressed, at Department of Gastroenterology, University Hospital, Building 1, C4P-012, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands.

Received 12/ 7/87. Revised 3/24/88. Accepted 5/ 2/88.

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