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Expression of Heterogeneous Profiles of Plasminogen Activators and Plasminogen Activator Inhibitors by Human Glioma Lines¹

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine [R. G. S., M. R. G., K. L. K.], and Department of Pathology, University of Michigan Medical Center [P. M., J. V.], Ann Arbor, Michigan 48109

Expression of plasminogen activator (PA) enzyme activity is believed to be one of the mechanisms by which malignant cells cause pericellular proteolysis of stromal structures during implantation and tissue invasion. In this study, four cell lines derived from human gliomas were studied to ascertain which PA enzymes and PA inhibitors determine the level of secreted PA activity. A plasminogen-dependent esterolytic assay was used, and two lines (U251 and U373) were found to secrete high levels of PA activity, while PA activity was undetectable in the conditioned media from the remaining two lines (U138 and LM). The PA produced by U251 and U373 resolved as single bands comigrating with high molecular weight urokinase (M_r 54,000) on casein-plasminogen zymography. Northern blot analysis demonstrated high levels of mRNA for urokinase-type PA (uPA) in U251 and U373, as well as a considerably lower level of uPA message in LM. U251 and U373 also contained mRNA for tissue-type PA (tPA), although secreted tPA activity was not demonstrated by zymography. The U138 line contained essentially undetectable levels of MRNA for either uPA or tPA. U138 was also unique in secreting PA inhibitor activity and contained high levels of mRNA for PA inhibitor 2, which was not seen in any other line. All cell lines contained PA inhibitor 1 mRNA, with substantially more expression in the U138 and LM lines than in U251 and U373. None of the lines secreted measureable anti-plasmin activity. We conclude that there is considerable heterogeneity among human glioma cells in expression of PA enzymes and PA inhibitors. The coordinated regulation of these proteins likely determines secreted PA activity and the resultant role of plasminogen activation in tumor implantation and invasion.

¹ Supported by grants from the National Heart, Lung, and Blood Institute (HL-01332 and HL-39672) and the American Cancer Society (ACS-432).

² To whom requests for reprints should be addressed, at Pulmonary & Critical Care Medicine Div., 3916 Taubman Center, Box 0360, Ann Arbor, MI 48109-0360.

Received 8/28/89. Revised 4/17/90.

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