Department of Urology, University of Washington, Seattle, WA 98195, USA.
Neoplasia. 2010 Feb;12(2):192-205. doi: 10.1593/neo.91836.
Bone morphogenetic protein (BMP) signaling is important in prostate development and prostate cancer (PCa) progression. However, because of the multiple effects of different BMPs, no final conclusions have been made as to the role of BMPs in PCa. In our studies, we have focused on BMP-7 because it is involved in prostate morphogenesis, and its expression is regulated by androgens. The objective of our study was to determine BMP-7 expression in PCa metastases and investigate the effects of BMP-7 on PCa cells. Our results show that BMP-7 is expressed in metastatic PCa and its levels are increased in castration-resistant PCa versus androgen-dependent PCa, whereas the expression of BMP-7 is decreased in primary PCa versus normal prostate. Our in vitro results show that BMP-7 inhibits proliferation of androgen-sensitive LNCaP cells, stimulates androgen receptor signaling, increases the expression of differentiation-associated genes, and decreases the levels of some wingless-regulated transcripts. Interestingly, these effects were not detected in C4-2 castration-resistant PCa cells. In vivo expression of BMP-7 in castration-resistant C4-2 cells did not alter proliferation when these cells were grown subcutaneously, but their growth was inhibited in the bone environment. In summary, our results show that BMP-7 is expressed at the highest level in advanced castration-resistant PCa cells and that the inhibitory effects of BMP-7 are dependent on the differentiation status of PCa cells and the tumor microenvironment. Further studies are needed to identify changes in BMP-7 signaling that lead to the loss of its control of proliferation during PCa progression.
骨形态发生蛋白（BMP）信号在前列腺发育和前列腺癌（PCa）进展中很重要。然而，由于不同 BMP 的多种作用，BMP 在 PCa 中的作用尚未得出最终结论。在我们的研究中，我们专注于 BMP-7，因为它参与前列腺形态发生，其表达受雄激素调节。我们研究的目的是确定 BMP-7 在 PCa 转移中的表达，并研究 BMP-7 对 PCa 细胞的影响。我们的结果表明，BMP-7 在转移性 PCa 中表达，并且在去势抵抗性 PCa 中比在雄激素依赖性 PCa 中其水平增加，而在原发性 PCa 中比在正常前列腺中其表达减少。我们的体外结果表明，BMP-7 抑制雄激素敏感性 LNCaP 细胞的增殖，刺激雄激素受体信号，增加分化相关基因的表达，并降低一些 Wnt 调控转录本的水平。有趣的是，这些作用在去势抵抗性 C4-2 PCa 细胞中未检测到。体内表达 BMP-7 在去势抵抗性 C4-2 细胞中不会改变这些细胞在皮下生长时的增殖，但在骨环境中它们的生长受到抑制。总之，我们的结果表明，BMP-7 在晚期去势抵抗性 PCa 细胞中表达水平最高，BMP-7 的抑制作用取决于 PCa 细胞的分化状态和肿瘤微环境。需要进一步的研究来确定导致 BMP-7 信号在 PCa 进展过程中失去对增殖控制的变化。
