Osteoblasts modulate secretion of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in human prostate cancer cells promoting migration and Matrigel invasion

Prostate carcinoma (PRCA) cells metastasize to the skeleton with high frequ ency. Bone stores growth regulatory factors, which are released in active f orm during bone remodeling. We propose that bone cell-derived growth factor s may induce the development of PRCA bone metastasis by recruiting tumor ce lls and increasing their proliferation in the bone microenvironment. Serum- free conditioned medium harvested from osteoblast cultures (OB Ch I) stimul ated the in vitro chemotaxis of PRCA cells and invasion of a reconstituted basement membrane (Matrigel), suggesting enhanced invasive activity. Preost eoblastic cell CMs were less effective than CMs obtained from mature OB. CM s harvested from differentiated osteoblast cultures capable of matrix miner alization were more active compared to CMs from proliferating osteoblasts. OB CMs stimulated secretion of urokinase (uPA) and matrix metalloproteinase -9 (MMP-9). Inhibition of these matrix-degrading proteases by neutralizing antibodies and/or by inhibitors of their catalytic activity reduced Matrige l invasion. Secretion of uPA and activation of MMP-9 were most prominent by differentiated OB CMs with respect to poorly differentiated cells in vitro . These results are in agreement with several in vivo studies and indicate that factors produced during osteogenesis by bone cells stimulate PRCA cell chemotaxis and matrix proteases expression, thus representing potential ta rgets for alternative therapies deterring the progression of PRCA metastasi s to bone.