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Endogenous Receptor-bound Urokinase Mediates Tissue Invasion of the Human Lung Carcinoma Cell Lines A549 and Calu-1¹

Department of Rheumatology and Immunology, Brigham and Women's Hospital [A. B., H. G. R.], Department of Pulmonary Medicine, New England Deaconess Hospital [A. E. F.], and Harvard Medical School [A. B., A. E. F., H. G. R.], Boston, Massachusetts 02115; and Departments of Orthopedics and Physiology, University of Vienna, Vienna, Austria [J. C. K., B. R. B.]

Macrophage colony-stimulating factor (CSF-1) increases the tissue invasive potential of the CSF-1 receptor-bearing lung carcinoma cell lines A549 and Calu-1 by increasing the number of endogenously bound urokinase-type plasminogen activators (u-PA)s on these cells. CSF-1, at concentrations which optimize invasion of A549 and Calu-1 cells into human amnion membranes (250 ng/ml), maximally augments the number of u-PA receptors occupied by endogenously produced urokinase. Preincubation of A549 and Calu-1 cells with the anti-u-PA monoclonal antibody MPW5UK (25 µg/ml) or with a 20- to 40-fold stoichiometric excess of fluid phase type 2 plasminogen activator inhibitor abrogates invasiveness, indicating that functionally active cell surface u-PA is essential for tissue invasion. In contrast, fluid phase type 1 plasminogen activator inhibitor (PAI-1, 5–15 units/ml) does not inhibit invasiveness unless preincubated with the amnion membranes. Inhibition of invasion by PAI-1 is abolished by presaturating the amnion membranes with anti-itronectin monoclonal antibody (10 µg/ml) which prevents binding of PAI-1 to tissue-associated vitronectin. Binding of PAI-1 to tissue vitronectin is therefore a prerequisite for its inhibitory action. Thus, endogenously receptor-bound u-PA is the primary protease mediating CSF-1-induced tissue invasiveness of the lung carcinoma cell lines A549 and Calu-1.

¹ Supported by National Institutes of Health Research Grant AI22532 and by a grant from the Oncology Foundation, University of Vienna, Austria.

² To whom requests for reprints should be addressed, at Department of Rheumatology/Immunology, Brigham and Women's Hospital, Room 513, LMRC, 221 Longwood Ave., Boston, MA 02115.

Received 11/ 1/91. Accepted 3/25/92.

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