Elucidation of the osteoblastic bone metastasis mechanism in human prostate cancer

我们建立了人成年骨片段异种移植，人前列腺癌细胞接种于人骨内的动物模型。利用这一动物模型，我们发现前列腺特异性抗原(PSA)作为一种丝氨酸蛋白酶，激活储存在骨基质中的各种生长因子，刺激成骨细胞，诱导破骨细胞凋亡，导致转移部位的成骨细胞发生显著变化。为了探讨PSA在成骨细胞改变中的具体作用机制，应用蛋白酶抑制剂对人前列腺癌来源的丝氨酸蛋白酶PSA进行失活。丝氨酸蛋白酶抑制剂治疗明显减少骨形成。这些结果表明PSA丝氨酸蛋白酶活性在前列腺癌的骨形成中起重要作用。除了PSA的骨形成作用外，PSA还可以激活储存在骨基质中的生长因子，如胰岛素样生长因子(IGF)。我们已经测试了PSA是否能切割IGF结合蛋白5(Igfbp5)，该蛋白与IGF形成复合体，主要储存在骨骼中。PSA以剂量依赖的方式切割Igfbp5并激活IGF信号转导。这些数据表明，前列腺癌产生的PSA激活了骨存储生长因子IGF和TGFb，促进了骨微环境中的骨形成和癌细胞存活。

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.