Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells.
Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells.
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DOI：
10.1083/jcb.139.7.1861
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发表时间：
1997-12-29
影响因子：
7.8
通讯作者：
Bissell, MJ
中科院分区：
文献类型：
--
作者：
Lochter, A;Galosy, S;Muschler, J;Freedman, N;Werb, Z;Bissell, MJ
基质金属蛋白酶（MMPs）调节乳腺上皮细胞的导管形态发生、凋亡和肿瘤进展。为了阐明基质金属蛋白酶对乳腺上皮的直接影响，我们产生了功能正常的细胞表达诱导型自激活基质溶解素-1（SL-1）转基因。SL-1表达的诱导导致E-钙粘蛋白的裂解，并触发进行性表型转化，其特征在于E-钙粘蛋白和连环蛋白从细胞-细胞接触中消失，细胞角蛋白的下调，波形蛋白的上调，角质形成细胞生长因子表达和活化的诱导，以及内源性MMP的上调。表达SL-1的细胞不能进行催乳分化，并变得具有侵袭性。一旦启动，这种表型转化基本上是稳定的，甚至在没有持续的SL-1表达的情况下也会进行。这些观察结果表明，SL-1的不适当表达启动了一系列事件，这些事件可能代表了一个协调的程序，导致分化上皮表型的丧失和肿瘤细胞某些特征的获得。我们的数据提供了新的见解MMPs如何在发展和肿瘤转化的功能。
Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apoptosis, and neoplastic progression in mammary epithelial cells. To elucidate the direct effects of MMPs on mammary epithelium, we generated functionally normal cells expressing an inducible autoactivating stromelysin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleavage of E-cadherin, and triggered progressive phenotypic conversion characterized by disappearance of E-cadherin and catenins from cell–cell contacts, downregulation of cytokeratins, upregulation of vimentin, induction of keratinocyte growth factor expression and activation, and upregulation of endogenous MMPs. Cells expressing SL-1 were unable to undergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed even in the absence of continued SL-1 expression. These observations demonstrate that inappropriate expression of SL-1 initiates a cascade of events that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics of tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.
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影响因子：
7.5
作者：
Basbaum, CB;Werb, Z
通讯作者：
Werb, Z
DOI：
10.1073/pnas.87.6.2279
发表时间：
1990-03-01
影响因子：
11.1
作者：
KANEMOTO, T;REICH, R;KLEINMAN, HK
通讯作者：
KLEINMAN, HK
影响因子：
6.4
作者：
LI, F;STRANGE, R;ANDRES, AC
通讯作者：
ANDRES, AC
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
15.9
作者：
GIJBELS, K;GALARDY, RE;STEINMAN, L
通讯作者：
STEINMAN, L