ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone.
ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone.
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DOI：
10.1158/0008-5472.can-13-1296
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Zijlstra A
中科院分区：
文献类型：
--
作者：
Hansen AG;Arnold SA;Jiang M;Palmer TD;Ketova T;Merkel A;Pickup M;Samaras S;Shyr Y;Moses HL;Hayward SW;Sterling JA;Zijlstra A
前列腺癌向骨的扩散是晚期疾病中一种常见的、无法治愈的方面。前列腺癌晚期的预防和治疗需要提高对这一过程的分子理解，以及分子进展的标志物。通过生化分析和体内功能缺失研究，我们证明了细胞粘附分子ALCAM在TGFβ的作用下，通过脱落酶ADAM17从转移性前列腺癌细胞中主动脱落。ALCAM的翻译后修饰不仅是前列腺癌进展的标志，也是有效骨转移所必需的分子。前列腺癌细胞的生化分析表明，ALCAM的表达和脱落在tgf - β信号的作用下升高。体外和体内的脱落均由ADAM17介导。对荷瘤小鼠循环ALCAM的纵向分析显示，在肿瘤生长过程中，肿瘤脱落而不是宿主来源的ALCAM升高。骨转移性PC3细胞中ALCAM基因特异性敲低可大大减少骨播散和骨肿瘤生长。ALCAM敲低细胞的生长减少与凋亡增加（Caspase-3）和增殖减少（Ki-67）相对应。综上所述，这些数据表明ALCAM既是功能调节剂，也是前列腺癌进展的标志物。
The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies we demonstrate that the cell adhesion molecule ALCAM is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGFβ. Not only is this post-translational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveal that ALCAM expression and shedding is elevated in response to TGFβ signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (Caspase-3) and decreased proliferation (Ki-67). Together these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.