Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
Cancer Res. 2012 Apr 1;72(7):1784-94. doi: 10.1158/0008-5472.CAN-11-3878. Epub 2012 Feb 16.
Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here, we report evidence of critical role for the angiopoietin-like protein 2 (ANGPTL2) in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In patients with lung cancer, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor cell-derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor cell-derived ANGPTL2 accelerated metastasis and shortened survival whereas attenuating ANGPTL2 expression in tumor cells-blunted metastasis and extended survival. Overall, our findings showed that tumor cell-derived ANGPTL2 drives metastasis and provided an initial proof of concept for blockade of its action as a strategy to antagonize the metastatic process.
抑制转移的策略在一定程度上主要由于缺乏机制上的理解而未能成功。在这里，我们报告了血管生成素样蛋白 2（ANGPTL2）在转移进展中起关键作用的证据。在小鼠中，ANGPTL2 已被牵连到炎症性致癌作用中，但尚未在人类肿瘤中进行研究。在肺癌患者中，原发性肿瘤中肿瘤细胞中 ANGPTL2 表达水平的升高与手术切除后无疾病生存时间的缩短有关。在侵袭性肿瘤细胞中上调的转录因子 NFATc、ATF2 和 c-Jun 促进了 Angptl2 的表达增加。值得注意的是，肿瘤细胞衍生的 ANGPTL2 以自分泌/旁分泌的方式增加了体外运动和侵袭性，赋予了侵袭性转移肿瘤表型。在异种移植小鼠模型中，肿瘤细胞衍生的 ANGPTL2 加速了转移并缩短了生存期，而抑制肿瘤细胞中的 ANGPTL2 表达则减弱了转移并延长了生存期。总的来说，我们的研究结果表明，肿瘤细胞衍生的 ANGPTL2 驱动转移，并为其作为抑制转移过程的策略的作用提供了初步的概念验证。
