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Malignant Transformation of Human Fibroblasts Correlates with Increased Activity of Receptor-bound Plasminogen Activator¹

Carcinogenesis Laboratory, Department of Microbiology and Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824-1316

To determine whether a relationship exists among urokinase plasminogen activator (u-PA) activity, tissue plasminogen activator (t-PA) activity, and the malignant transformation of human fibroblasts, we measured receptor-bound and secreted u-PAs and t-PA activity in fibroblast cell strains of a unique cell lineage and compared the results with the values obtained in human fibrosarcoma-derived cell lines and control cell lines. The lineage consists of four nonmalignant, infinite life span cell strains, clonally derived from a finite life span, neonatal foreskin-derived cell line or one of its derivatives and 10 malignant cell strains clonally derived from that same derivative. Seven of the latter were malignantly transformed by K-, H-, or N-ras oncogene transfection, two were obtained following carcinogen treatment, and one arose spontaneously. All 10 malignant strains in this lineage exhibited significantly higher levels of activity of receptor-bound u-PA than was found in the cell strain from which they arose or the nonmalignant cell strains derived from it. The ras oncogene-transformed malignant strains also exhibited significantly higher levels of activity of receptor-bound t-PA than their cell strain of origin. The other three malignant strains showed undetectable levels, consistent with their attaining the malignant state by an alternate process. The five fully malignant fibrosarcoma-derived cell lines tested also showed high levels of receptor-bound u-PA and t-PA. The majority (80%) of the nonmalignant control cell lines did not do so. The 10 malignant cell strains in the lineage also exhibited higher levels of activity of secreted high molecular weight u-PA or t-PA than did their cell strain of origin and the nonmalignant cell strains derived from it, as did the malignant fibrosarcoma-derived cell lines. The data suggest that the malignant state of human fibroblasts is always associated with high levels of activity of receptor-bound u-PA, and in addition cells transformed to the malignant state are very likely to exhibit high levels of receptorbound t-PA and secreted forms of plasminogen activators.

¹ Supported by Department of Health and Human Services Grant CA 21289 from the National Cancer Institute and Department of Energy Grant ER-60524.

² Present address: Chemistry Department, University of Toledo, Toledo, OH 43606-3390.

³ To whom requests for reprints should be addressed, at Carcinogenesis Laboratory, Free Hall, Michigan State University, East Lansing, MI 48824-1316.

Received 3/ 5/90. Accepted 11/28/90.

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