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Elucidation of the osteoblastic bone metastasis mechanism in human prostate cancer

阐明人类前列腺癌成骨细胞骨转移机制

基本信息

批准号：
16590332
负责人：
OCHIAI Atsushi
金额：
$ 2.24万
依托单位：
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

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.

我们建立了一种动物模型，其中将人成人骨碎片异种移植并将人前列腺癌细胞接种到人骨中。使用该动物模型，我们发现前列腺特异性抗原（PSA）作为丝氨酸蛋白酶激活储存在骨基质中的各种生长因子，刺激成骨细胞并诱导破骨细胞凋亡，导致转移部位显著的成骨细胞变化。为了研究PSA对成骨细胞变化的详细机制，将蛋白酶抑制剂应用于人前列腺癌来源的丝氨酸蛋白酶--PSA。丝氨酸蛋白酶抑制剂治疗显着减少骨形成。这些结果表明PSA的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对骨形成的作用外，PSA还可作为储存在骨基质中的生长因子（如胰岛素样生长因子（IGF））的激活剂。我们已经测试了PSA是否切割IGF结合蛋白5（IGFBP 5），其与IGF形成复合物并且主要储存在骨骼中。PSA以剂量依赖性方式切割IGFBP 5并激活IGF信号传导。这些数据表明，由人前列腺癌产生的PSA激活骨储存生长因子，如IGF和TGF β，并刺激骨形成和骨微环境中的癌细胞存活。