Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition.
Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition.
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在乳腺中，基质细胞外基质（ECM）在发育和肿瘤发生过程中发生了巨大变化。例如，正常成人乳腺组织基本上缺乏ECM蛋白纤连蛋白（FN），而在乳腺肿瘤的基质中检测到高FN水平。FN是上皮-间充质转化（EMT）的既定标志物，EMT发生在发育过程中，并与癌症有关。在EMT过程中，上皮细胞粘附从细胞-细胞接触转变为主要的细胞-ECM相互作用，这增加了FN可能在促进这种转变中发挥作用的可能性。使用MCF-10A乳腺上皮细胞，我们发现暴露于外源性FN诱导EMT反应，包括EMT标志物FN、Snail、N-cadherin、波形蛋白、基质金属蛋白酶MMP 2、α-平滑肌肌动蛋白和磷酸化Smad 2的上调以及细胞迁移行为的获得。FN诱导的EMT依赖于Src激酶和ERK/MAP激酶信号，但不依赖于立即早期基因EGR-1。FN在无血清条件下启动EMT;该反应可被TGFβ中和抗体部分逆转，表明FN增强内源性TGFβ的作用。EMT标志物表达在细胞中在含有整联蛋白结合结构域但不含其它结构域的FN片段上上调。FN和MG之间基因表达的差异通过添加亚阈值水平的TGFβ1而得以维持。总之，这些结果表明，与FN相互作用的细胞被启动以响应TGFβ。FN诱导EMT的能力显示了基质ECM在此过程中的积极作用，并支持在乳腺肿瘤中观察到的FN水平升高促进肿瘤发生的观点。
In the mammary gland, the stromal extracellular matrix (ECM) undergoes dramatic changes during development and in tumorigenesis. For example, normal adult breast tissue is largely devoid of the ECM protein fibronectin (FN) whereas high FN levels have been detected in the stroma of breast tumors. FN is an established marker for epithelial-mesenchymal transition (EMT), which occurs during development and has been linked to cancer. During EMT, epithelial cell adhesion switches from cell-cell contacts to mainly cell-ECM interactions raising the possibility that FN may have a role in promoting this transition. Using MCF-10A mammary epithelial cells, we show that exposure to exogenous FN induces an EMT response including up-regulation of the EMT markers FN, Snail, N-cadherin, vimentin, the matrix metalloprotease MMP2, α-smooth muscle actin, and phospho-Smad2 as well as acquisition of cell migratory behavior. FN-induced EMT depends on Src kinase and ERK/MAP kinase signaling but not on the immediate early gene EGR-1. FN initiates EMT under serum-free conditions; this response is partially reversed by a TGFβ neutralizing antibody suggesting that FN enhances the effect of endogenous TGFβ. EMT marker expression is up-regulated in cells on a fragment of FN containing the integrin-binding domain but not other domains. Differences in gene expression between FN and MG are maintained with addition of a sub-threshold level of TGFβ1. Together, these results show that cells interacting with FN are primed to respond to TGFβ. The ability of FN to induce EMT shows an active role for the stromal ECM in this process and supports the notion that the increased levels of FN observed in breast tumors facilitate tumorigenesis.
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