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Volume 272, Number 27, Issue of July 4, 1997 pp. 17216-17222
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Urokinase Plasminogen Activator and Gelatinases Are Associated with Membrane Vesicles Shed by Human HT1080 Fibrosarcoma Cells

(Received for publication, February 3, 1997, and in revised form, April 28, 1997)

Angela Ginestra , Sara Monea ^§ , Graziano Seghezzi ^§ , Vincenza Dolo , Hideaki Nagase ^** , Paolo Mignatti ^§ and M. Letizia Vittorelli ^§§

From the ^§ Department of Cellular and Developmental Biology, University of Palermo, Italy 90128, ^§ Department of Genetics and Microbiology, University of Pavia, Italy, 27100  Department of Experimental Medicine, University of L'Aquila, Italy 67010, ^** Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, and ^§§ COBS (Centro di Oncobiologia Sperimentale), Palermo, Italy 90128

Membrane vesicles are shed by tumor cells both in vivo and in vitro. Although their functions are not well understood, it has been proposed that they may play multiple roles in tumor progression. We characterized membrane vesicles from human HT1080 fibrosarcoma cell cultures for the presence of proteinases involved in tumor invasion. By gelatin zymography and Western blotting, these vesicles showed major bands corresponding to the zymogen and active forms of gelatinase B (MMP-9) and gelatinase A (MMP-2) and to the MMP-9·tissue inhibitor of metalloproteinase 1 complex. Both gelatinases appeared to be associated with the vesicle membrane. HT1080 cell vesicles also showed a strong, plasminogen-dependent fibrinolytic activity in ¹²⁵I fibrin assays; this activity was associated with urokinase plasminogen activator, as shown by casein zymography and Western blotting. Urokinase was bound to its high affinity receptor on the vesicle membrane. Addition of plasminogen resulted in activation of the progelatinases associated with the vesicles, indicating a role of the urokinase-plasmin system in MMP-2 and MMP-9 activation. We propose that vesicles shed by tumor cells may provide a large membrane surface for the activation of membrane-associated proteinases involved in extracellular matrix degradation and tissue invasion.

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