Elucidation of the osteoblastic bone metastasis mechanism in human prostate cancer

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We have established an animal model in which human adult bone fragments were xenotransplanted and human prostate cancer cells were inoculated into human bone. Using this animal model we have found that prostate specific antigen (PSA) works as a serine protease to activate various growth factors that are stored in bone matrix and stimulate osteoblasts and induce apoptosis of osteoclasts, resulting marked osteoblastc change at metastatic sites. In order to investigate detail mechanisms of PSA on osteoblastic changes, protease inhibitors were applied to inactivate PSA as a serine protease derived from human prostate cancer. Serine protease inhibitors treatment markedly reduced bone formation. These results indicate that serine protease activity of PSA plays an important role on bone formation in prostate cancer. In addition to the PSA effect of bone formation, PSA works as an activator of growth factors stored in bone matrix, such as insulin-like growth factor (IGF). We have tested whether PSA cleaved IGF binding protein 5 (IGFBP5) that makes a complex with IGF and is mainly stored in bone. PSA cleaved IGFBP5 in a dose dependent manner and activated IGF signaling. These data indicate that PSA produced by human prostate cancer activates bone stored growth factors such as IGF and TGFb and stimulates bone formation and cancer cell survival in bone microenvironment.