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Modulation of Metastatic Potential by Cell Surface Urokinase of Murine Melanoma Cells¹

Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [V. J. H., L. W. L., E. A.]; Lepetit Research Laboratories, Gerenzano, Varese, Italy [A. C.]; and International Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Via Marconi 10, 80123 Naples, Italy [F. B.]

We have carried out enzymatic, immunofluorescence, and surface iodination studies which show that B16 melanoma cells express the single chain form of the urokinase type plasminogen activator (uPA) on their cell surface, and that these cells are capable of plasminogen-dependent fibronectin degradation. The significance of the expression of surface single-chain uPA and uPA activity to the metastatic process was examined by preincubating melanoma cells with uPA modulating agents followed by i.v. injection of the cells into mice and enumeration of pulmonary nodules 17 days later. B16 cells that had been pretreated with anti-uPA immunoglobulins that were inhibitory to uPA activity invariably showed significantly decreased numbers of metastases compared to controls. On the contrary, pretreatment with plasmin, which is not only the product of the uPA catalyzed reaction but is also able to convert single-chain uPA to uPA, significantly increased the numbers of metastases. Control treatments, which included normal rabbit and mouse immunoglobulins, monovalent noninhibitory anti-uPA Fab fragments, and various monoclonal and polyclonal antibodies directed against other B16 cell surface antigens, did not affect the metastatic potential of the cells. Divalent inhibitory anti-uPA F(ab)₂ fragments, on the contrary, inhibited metastasis as efficiently as intact IgG. The results support the hypothesis that proteolysis of extracellular matrix components by cell surface-localized uPA may be a critical step during the process of tumor cell invasion and metastasis.

¹ Work carried out in Italy was supported by Progetto Finalizzato Oncologia and P. F. Ingegneria Genetica Consiglio Nazionale delle Ricerche.

² To whom requests for reprints should be addressed, at Bldg. 37, Room 1B22, National Cancer Institute, NIH, Bethesda, MD 20892.

³ Fogarty Scholar in Residence, NIH, Bethesda, MD, during portions of this work.

Received 8/10/87. Revised 11/19/87. Accepted 11/30/87.

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