C. Festuccia et al., Osteoblast-derived TGF-beta 1 modulates matrix degrading protease expression and activity in prostate cancer cells, INT J CANC, 85(3), 2000, pp. 407-415
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.