Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis
Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis
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DOI：
10.1158/0008-5472.can-16-0176
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Garcia de Herreros, Antonio
中科院分区：
文献类型：
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作者：
Alba-Castellon, Lorena;Olivera-Salguero, Ruben;Garcia de Herreros, Antonio
Snail 1转录因子是触发上皮细胞向间质细胞转化（EMT）和诱导肿瘤细胞侵袭所必需的。我们在这里报告了Snail 1对肿瘤侵袭的EMT独立作用，因为它是激活癌症相关成纤维细胞（CAF）所必需的。Snail 1在成纤维细胞中的表达需要来自肿瘤细胞的信号，例如TGF β;在成纤维细胞中，Snail 1组织了一个复杂的程序，该程序刺激上皮细胞的侵袭，而不依赖于Snail 1在这些细胞中的表达。上皮细胞的侵袭受到成纤维细胞分泌的可扩散的信号分子如前列腺素E2的刺激。人或鼠CAF促进肿瘤侵袭的能力依赖于Snail 1表达。小鼠中可诱导的Snail 1缺失降低了乳腺肿瘤的侵袭性;此外，上皮肿瘤细胞与Snail 1缺失的成纤维细胞共异种移植产生的肿瘤的侵袭性低于与对照成纤维细胞移植的肿瘤。因此，这些结果表明，Snail 1在肿瘤侵袭中的作用不仅限于EMT，而且还依赖于其在基质成纤维细胞中的活性，在基质成纤维细胞中，Snail 1与上皮肿瘤细胞发生了相互作用。
Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here an EMT-independent action of Snail1 on tumor invasion, as it is required for the activation of cancer-associated fibroblasts (CAF). Snail1 expression in fibroblasts requires signals derived from tumor cells, such as TGF beta; reciprocally, in fibroblasts, Snail1 organizes a complex program that stimulates invasion of epithelial cells independent of the expression of Snail1 in these cells. Epithelial cell invasion is stimulated by the secretion by fibroblast of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine CAFs to promote tumor invasion is dependent on Snail1 expression. Inducible Snail1 depletion in mice decreases the invasion of breast tumors; moreover, epithelial tumor cells coxenografted with Snail1-depleted fibroblasts originated tumors with lower invasion than those transplanted with control fibroblasts. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to EMT, but it is also dependent on its activity in stromal fibroblasts, where it orchestrates the cross-talk with epithelial tumor cells.