Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer.
Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer.
复制标题
需要上皮钙粘着蛋白的下调以引发乳腺癌的转移性生长。
DOI：
10.1091/mbc.e11-04-0306
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发表时间：
2011-07-15
影响因子：
3.3
通讯作者：
Schiemann WP
中科院分区：
文献类型：
--
作者：
Wendt MK;Taylor MA;Schiemann BJ;Schiemann WP
转化生长因子β及其对上皮间质转化的调节通过下调上皮钙粘蛋白参与肺转移瘤的生长。上皮钙粘蛋白（E-cad）减少是获得上皮间质转化（EMT）表型的浸润性癌的标志。在这里，我们表明，下调E-cad表达诱导的转化生长因子-β（TGF-β）和EMT乳腺癌生长之前，在三维（3D）器官型测定和小鼠肺。针对黏着斑激酶的药理学抑制剂可防止新接种的类器官的转移性生长，但不能防止其完全建立的对应物的转移性生长。对乳腺癌休眠和转移的D2-HAN（增生性肺泡结节）模型的研究表明，休眠的D2.OR细胞在3D培养物中产生分支的类器官形态，并表达大量与TGF-β调节解偶联的E-cad。相反，转移性D2.A1类器官是球形的，完全缺乏E-cad表达。有趣的是，经工程改造以重新表达E-cad的D2.A1细胞形成分支类器官，下调β 1整联蛋白表达，并且未能经历转移性生长。E-cad的肿瘤抑制功能通过增加微环境刚性而失活，并且不通过缺乏其胞外结构域的E-cad突变体的表达而被重演。Twist的表达，而不是Snail的表达，在休眠的D2.OR细胞中重新启动了转移性生长。我们的研究结果表明，EMT及其下调的E-cad表达部分通过促进转移性生长所必需的β 1整合素表达来规避乳腺癌休眠。
Transforming growth factor β and its regulation of epithelial mesenchymal transition contribute to the initiation of pulmonary metastatic outgrowth specifically through the down-regulation of epithelial cadherin. Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-β (TGF-β) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D-cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-β. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re-express E-cad formed branched organoids, down-regulated β1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating β1 integrin expression necessary for metastatic outgrowth.