An in vivo model of epithelial to mesenchymal transition reveals a mitogenic switch.
An in vivo model of epithelial to mesenchymal transition reveals a mitogenic switch.
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DOI：
10.1016/j.canlet.2012.08.013
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发表时间：
2012-12-30
期刊：
影响因子：
9.7
通讯作者：
Law, Brian K.
中科院分区：
文献类型：
--
作者：
Jahn, Stephan C.;Law, Mary E.;Corsino, Patrick E.;Parker, Nicole N.;Pham, Kien;Davis, Bradley J.;Lu, Jianrong;Law, Brian K.
上皮向间充质转化(EMT)是分化上皮细胞向间充质表型转化的过程。EMT使上皮细胞能够从组织结构的严格结构限制中逃脱到更易于细胞迁移的表型，从而更容易侵袭和转移。我们描述了EMT的体内模型，并发现在这个过程中有丝分裂信号发生了显著的变化。DNA微阵列分析显示，EMT后和EMT前的乳腺癌细胞中，许多基因的表达存在显著差异。EMT后的癌细胞上调了编码c-Met、PDGF和LPA受体的mRNA，并获得了对HGF、PDGF和LPA的反应性增强。这使得EMT后的细胞对HGF、PDGF和LPA受体抑制剂/拮抗剂的生长抑制作用有反应。此外，EMT后细胞表现出基础Raf和ERK磷酸化降低，与EMT前细胞相比，MEK抑制剂对它们的增殖抑制作用较差。这些研究表明，治疗方法需要针对EMT前和EMT后的癌细胞，EMT后细胞的信号变化可能允许它们利用体内间质的旁分泌信号。
The epithelial to mesenchymal transition (EMT) is a process by which differentiated epithelial cells transition to a mesenchymal phenotype. EMT enables the escape of epithelial cells from the rigid structural constraints of the tissue architecture to a phenotype more amenable to cell migration and, therefore, invasion and metastasis. We characterized an in vivo model of EMT and discovered that marked changes in mitogenic signaling occurred during this process. DNA microarray analysis revealed that the expression of a number of genes varied significantly between post-EMT and pre-EMT breast cancer cells. Post-EMT cancer cells upregulated mRNA encoding c-Met and the PDGF and LPA receptors, and acquired increased responsiveness to HGF, PDGF, and LPA. This rendered the post-EMT cells responsive to the growth inhibitory effects of HGF, PDGF, and LPA receptor inhibitors/antagonists. Furthermore, post- EMT cells exhibited decreased basal Raf and Erk phosphorylation, and in comparison to pre-EMT cells, their proliferation was poorly inhibited by a MEK inhibitor. These studies suggest that therapies need to be designed to target both pre-EMT and post-EMT cancer cells and that signaling changes in post- EMT cells may allow them to take advantage of paracrine signaling from the stroma in vivo.
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影响因子：
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作者：
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DOI：
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发表时间：
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