Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition.
Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition.
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DOI：
10.1186/1476-4598-9-179
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发表时间：
2010-07-07
期刊：
影响因子：
37.3
通讯作者：
Wells A
中科院分区：
文献类型：
--
作者：
Chao YL;Shepard CR;Wells A
上皮向间充质转化（EMT）是肿瘤传播的一种机制，其特征是e -钙粘蛋白的缺失、细胞粘附的破坏以及细胞运动和侵袭的诱导。在大多数导管内乳腺癌中，e -钙粘蛋白是通过启动子甲基化进行表观遗传调控的。因此，e -钙粘蛋白的表达是动态的，并受微环境的调节。此外，已经观察到转移灶通常比原发肿瘤分化程度更高，这表明癌细胞可能在EMT后的继发器官环境中进一步经历间充质到上皮细胞的转化（MErT），从而允许逃逸。我们首先检测了E-cadherin在乳腺原发肿瘤及其相应的肝、肺和脑转移灶中的表达，发现62%（10/16）的转移灶中E-cadherin的表达高于原发灶。这些观察结果导致了一个问题，即阳性转移灶是由e -cadherin阳性细胞的扩增引起的，还是由最初e -cadherin阴性播散细胞的MErT引起的。因此，我们的目的是确定间充质样MDA-MB-231乳腺癌细胞是否可能通过外源导入或微环境诱导，通过E-cadherin的重新表达经历MErT。全长E-cadherin在MDA-MB-231细胞中的异位表达导致上皮表型的形态和功能逆转，甚至只是E-cadherin的细胞质结构域产生部分表型。将MDA-MB-231细胞或原代外植体导入由肝细胞共培养系统模拟的二级器官环境中，通过启动子甲基化的被动丢失诱导E-cadherin重新表达。此外，注射到小鼠乳腺脂肪垫的MDA-MB-231细胞自发转移后检测到e- cadherin阳性转移灶，表明这种重新表达是功能性的。我们的临床观察和实验数据表明，二级器官微环境可以诱导E-cadherin的重新表达，从而诱导MErT。这种表型变化反映在细胞行为的改变上，因此可能是转移部位细胞存活的关键步骤。
Epithelial to mesenchymal transition (EMT), implicated as a mechanism for tumor dissemination, is marked by loss of E-cadherin, disruption of cell adhesion, and induction of cell motility and invasion. In most intraductal breast carcinomas E-cadherin is regulated epigenetically via methylation of the promoter. E-cadherin expression is therefore dynamic and open to modulation by the microenvironment. In addition, it has been observed that metastatic foci commonly appear more differentiated than the primary tumor, suggesting that cancer cells may further undergo a mesenchymal to epithelial reverting transition (MErT) in the secondary organ environment following the EMT that allows for escape. We first examined E-cadherin expression in primary breast tumors and their corresponding metastases to liver, lung and brain and discovered that 62% (10/16) of cases showed increased E-cadherin expression in the metastases compared to the primaries. These observations led to the question of whether the positive metastatic foci arose from expansion of E-cadherin-positive cells or from MErT of originally E-cadherin-negative disseminated cells. Thus, we aimed to determine whether it was possible for the mesenchymal-like MDA-MB-231 breast cancer cells to undergo an MErT through the re-expression of E-cadherin, either through exogenous introduction or induction by the microenvironment. Ectopic expression of full-length E-cadherin in MDA-MB-231 cells resulted in a morphological and functional reversion of the epithelial phenotype, with even just the cytosolic domain of E-cadherin yielding a partial phenotype. Introduction of MDA-MB-231 cells or primary explants into a secondary organ environment simulated by a hepatocyte coculture system induced E-cadherin re-expression through passive loss of methylation of the promoter. Furthermore, detection of E-cadherin-positive metastatic foci following the spontaneous metastasis of MDA-MB-231 cells injected into the mammary fat pad of mice suggests that this re-expression is functional. Our clinical observations and experimental data indicate that the secondary organ microenvironment can induce the re-expression of E-cadherin and consequently MErT. This phenotypic change is reflected in altered cell behavior and thus may be a critical step in cell survival at metastatic sites.
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影响因子：
10.5
作者：
HOLLER, M;WESTIN, G;SCHAFFNER, W
通讯作者：
SCHAFFNER, W
影响因子：
11.2
作者：
Chaffer, Christine L.;Brennan, Janelle P.;Williams, Elizabeth D.
通讯作者：
Williams, Elizabeth D.
影响因子：
2.7
作者：
Kokkinos, Maria I.;Wafai, Razan;Waltham, Mark
通讯作者：
Waltham, Mark
DOI：
10.1186/bcr651
发表时间：
2003
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kowalski PJ;Rubin MA;Kleer CG
通讯作者：
Kleer CG
影响因子：
3.5
作者：
Goldstein, NS
通讯作者：
Goldstein, NS