Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism
Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism
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DOI：
10.1158/0008-5472.can-05-1891
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Keller, ET
中科院分区：
文献类型：
--
作者：
Dai, JL;Keller, J;Keller, ET
前列腺癌经常转移到骨，在那里它通过未知的机制形成成骨细胞病变。骨形态发生蛋白（BMP）是骨骼形成的介质。前列腺癌产生多种BMP，包括BMP-6。我们检验了BMP-6在前列腺癌骨转移部位引起骨质增生的假设。前列腺癌细胞和临床组织产生的BMP-6随着肿瘤的侵袭性而增加。前列腺癌的条件培养基诱导SMAD磷酸化的前成骨细胞MC 3 T3细胞，和磷酸化的抗BMP-6抗体减弱。前列腺癌条件培养基诱导MC 3 T3细胞的矿化，这被BNIP抑制剂头蛋白和抗BMP-6阻断。将人胎儿骨植入严重的联合免疫缺陷小鼠中，4周后，将LuCaP 23.1前列腺癌细胞皮下注射到小鼠的皮下和皮下。并进入骨植入物。然后开始施用抗BMP-6或同种型抗体。抗BMP-6降低LuCaP 23.1诱导的成骨细胞活性，但对其溶骨活性没有影响。根据骨组织形态计量学评价，这与成骨细胞数量和成骨细胞活性增加有关。由于内皮素-1与骨转移有关，我们测定了血清内皮素-1水平，但发现治疗组间无差异。除了减少骨生成，抗BMP-6减少骨内，但不s.c.，肿瘤大小我们发现BMP-2、BMP-4、BMP-6、BMP-7对前列腺癌细胞的生长没有直接的影响，但BMP-2、BMP-6可增强前列腺癌细胞的体外侵袭能力。这些数据表明，前列腺癌通过BMP-6促进成骨细胞活性，并且除了其骨效应之外，还表明BMP促进前列腺癌细胞侵入骨微环境的能力。
Prostate cancer frequently metastasizes to bone where it forms osteoblastic lesions through unknown mechanisms. Bone morphogenetic proteins (BMP) are mediators of skeletal formation. Prostate cancer produces a variety of BMPs, including BMP-6. We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites. Prostate cancer cells and clinical tissues produced BMP-6 that increased with aggressiveness of the tumor. Prostate cancer-conditioned medium induced SMAD phosphorylation in the preosteoblast MC3T3 cells, and phosphorylation was diminished by anti-BMP-6 antibody. Prostate cancer-conditioned medium induced mineralization of MC3T3 cells, which was blocked by both the BNIP inhibitor noggin and anti-BMP-6. Human fetal bones were implanted in severe combined immunodeficient mice and after 4 weeks, LuCaP 23.1 prostate cancer cells were injected both s.c. and into the bone implants. Anti-BMP-6 or isotype antibody administration was then initiated. Anti-BMP-6 reduced LuCaP 23.1-induced osteoblastic activity, but had no effect on its osteolytic activity. This was associated with increased osteoblast numbers and osteoblast activity based on bone histomorphometric evaluation. As endothelin-1 has been implicated in bone metastases, we measured serum endothelin-1 levels but found they were not different among the treatment groups. In addition to decreased bone production, anti-BMP-6 reduced intraosseous, but not s.c., tumor size. We found that BMP-2, BMP-4, BMP-6, and BMP-7 had no direct effect on prostate cancer cell growth, but BMP-2 and BMP-6 increased the in vitro invasive ability of prostate cancer cell. These data show that prostate cancer promotes osteoblastic activity through BMP-6 and that, in addition to its bone effects, suggest that BMPs promote the ability of the prostate cancer cells to invade the bone microenvironment.