Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, Bethesda, Maryland, United States of America ; Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
PLoS One. 2013 Aug 14;8(8):e71709. doi: 10.1371/journal.pone.0071709. eCollection 2013.
Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.
前列腺癌（PC）是男性死亡的主要原因，但是调节其进展并最终转移到骨骼的因素仍不清楚。在这里，我们显示在前列腺癌组织中，WISP1/CCN4 的表达在疾病的早期阶段上调，并且进一步显示其与疾病早期患者血清中 WISP1 的循环水平增加相关。WISP1 在小鼠前列腺癌模型 TRAMP 中也在发育为晚期癌之前的发育不良病变组织中升高。当测试抗 WISP1 抗体减少 PC3-Luc 细胞向远处部位扩散的能力时，发现每周两次注射抗 WISP1 抗体可减少在小鼠心脏内（IC）注射 PC3-Luc 细胞后远处肿瘤的数量和总体大小。还评估了针对 WISP1 的抗体抑制小鼠中 PC3-Luc 癌细胞生长的能力，并发现每周两次注射抗 WISP1 抗体可减少异种移植物中局部肿瘤的生长。为了更好地了解作用机制，通过带有或不带有 Matrigel™屏障的膜研究了 PC3-Luc 细胞的迁移，结果表明细胞被 WISP1 吸引，并且这种吸引力被抗 WISP1 抗体的处理所抑制。我们还显示了在骨肿瘤界面和早期癌症基质中 WISP1 的表达，表明 WISP1 的表达非常适合在促进癌症生长及其向骨骼扩散中发挥作用。总之，WISP1 在癌症发展的早期阶段上调，加上其抑制前列腺癌细胞扩散和生长的能力，使其成为前列腺癌的潜在靶标和可及的诊断标志物。
