THROMBOSPONDIN (TSP) AND TRANSFORMING GROWTH-FACTOR-BETA-1 (TGF-BETA)PROMOTE HUMAN A549 LUNG-CARCINOMA CELL PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 (PAL-1) PRODUCTION AND STIMULATE TUMOR-CELL ATTACHMENT IN-VITRO

A growing body of evidence has recently implicated TSP and TGF-beta in the process of malignancy, such as tumor cell proliferation, tumor an giogenesis, and metastasis. The purpose of the present study was to ev aluate potential mechanisms of TSP and TGF-beta in tumor cell attachme nt and invasion. Our results indicate that both TSP and TGF-beta promo ted tumor cell attachment and spreading in the presence of plasminogen . The mechanism for these effects appeared to be due, in part, to the capacity of TSP and TGF-beta to induce tumor cell production of (PAI-1 ). PAI-1, which is a natural inhibitor of tumor-cell associated urokin ase-type plasminogen activator (uPA) activity, inhibited activation of plasminogen to plasmin in the growth media,thereby preventing plasmin -induced detachment of cells. The TSP-promoted production of PAI-1 cou ld be inhibited not only by anti-TSP antibodies but also by a neutrali zing antibody against TGF-beta. These results suggest that TSP by a me chanism involving TGF-beta can promote cell adhesion through stimulati on of tumor cell secretion of PAI-1. These data provide evidence that TSP not only has the capacity of functioning as a matrix protein to di rectly promote cell-substratum adhesion but that TSP can also stimulat e cell adhesion and spreading by modulating cell surface protease expr ession through stimulation of tumor-associated production of PAI-1. (C ) Academic Press, Inc.