Osteoblast-derived TGF-beta 1 modulates matrix degrading protease expression and activity in prostate cancer cells

Tumor progression and metastasis may result in part from the selection of c ell clones competent for survival, invasion and growth at secondary sites a cid characterized by loss of growth inhibitory responses, acquisition of in creased adhesiveness and enhanced motility and protease expression. Transfo rming growth factor-beta 1 (TGF-beta 1) is produced by osteoblasts (OB) in a latent form and is activated by proteases in a cell-dependent manner, We show here that OB conditioned medium (OB CM) modulates Matrigel invasion of a bone metastatic prostate cancer cell line (PC3) and that this effect is blocked by antibody against TGF-beta 1 and by uPA/plasmin inhibitors, sugge sting that TGF-beta 1 can modulate OB-mediated cell recruitment and that PC 3 cells can activate TGF-beta 1. TGF-beta 1 induces uPA and PAI-I secretion and promotes binding of uPA at the external plasma membrane with increased membrane-associated plasmin activity. Matrix metalloprotease-9 (MMP-9) is induced both in the medium and in the membrane associated form. Moreover, t he balance between proteolytic activity and inhibition is crucial in the me tastatic event. Indeed, the increment of PAI-I could have an important regu latory role on the extracellular proteolysis and might explain the decrease of net PA and gelatinolytic activities measured in the medium. In addition , PAI-I plays a regulative role localizing matrix degradation in some speci fic sites, such as areas of cell-to-cell or cell-to-ECM contacts. In conclu sion, TGF-beta 1 enhances PC3 Matrigel invasion by a uPA/plasmin-dependent mechanism, also involving the MMP-9, and thus may play a central role in ma lignant prostate tumor progression as a result of stimulating bone matrix i nvasion. (C) 2000 Wiley-Liss, Inc.