Thrombospondin (TSP) and Transforming Growth Factor β 1 (TGF-β) 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-β in the process of malignancy, such as tumor cell proliferation, tumor angiogenesis, and metastasis. The purpose of the present study was to evaluate potential mechanisms of TSP and TGF-β in tumor cell attachment and invasion. Our results indicate that both TSP and TGF-β promoted 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-β to induce tumor cell production of (PAI-1). PAI-1, which is a natural inhibitor of tumor-cell associated urokinase-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 could be inhibited not only by anti-TSP antibodies but also by a neutralizing antibody against TGF-β. These results suggest that TSP by a mechanism involving TGF-β can promote cell adhesion through stimulation 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 directly promote cell-substratum adhesion but that TSP can also stimulate cell adhesion and spreading by modulating cell surface protease expression through stimulation of tumor-associated production of PAI-1.