Thrombospondin (TSP) and transforming growth factor beta 1 (TGF-beta) promote human A549 lung carcinoma cell plasminogen activator inhibitor type 1 (PAI-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 angiogenesis, and metastasis. The purpose of the present study was to evaluate potential mechanisms of TSP and TGF-beta in tumor cell attachment and invasion. Our results indicate that both TSP and TGF-beta 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-beta 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-beta. These results suggest that TSP by a mechanism involving TGF-beta 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.
Albo
D
D
Medical College of Pennsylvania, Department of Surgery (Plastic), Philadelphia 19129.
Arnoletti
J P
JP
Castiglioni
A
A
Granick
M S
MS
Solomon
M P
MP
Rothman
V L
VL
Tuszynski
G P
GP
D000230:Adenocarcinoma / Q000378:metabolism*; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000276:immunology; D019699:Thrombospondins; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D000906:Antibodies; D008562:Membrane Glycoproteins; D017395:Plasminogen Activator Inhibitor 1; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator