Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
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DOI：
10.1083/jcb.201704053
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发表时间：
2017-11-06
期刊：
影响因子：
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通讯作者：
Webb DJ
中科院分区：
文献类型：
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作者：
Erdogan B;Ao M;White LM;Means AL;Brewer BM;Yang L;Washington MK;Shi C;Franco OE;Weaver AM;Hayward SW;Li D;Webb DJ
肿瘤间质中的癌症相关成纤维细胞（CAF）在肿瘤进展中发挥关键作用。Erdogan等人表明，CAF介导的纤连蛋白基质排列是促进癌细胞定向迁移的关键因素。癌相关成纤维细胞（CAF）是促进肿瘤进展的癌微环境的主要成分。然而，CAFs调节癌细胞迁移的机制知之甚少。在这项研究中，我们表明，纤维连接蛋白（Fn）组装的CAFs介导的CAF-癌细胞协会和定向迁移。与正常成纤维细胞相比，CAFs产生富含Fn的具有各向异性纤维取向的细胞外基质，其引导癌细胞定向迁移。CAF通过增加非肌肉肌球蛋白II和血小板衍生生长因子受体α介导的收缩力和牵引力（通过α5β1整联蛋白转导为Fn）排列Fn基质。我们进一步表明，前列腺癌细胞使用αv整合素在CAF衍生的基质上有效和定向地迁移。我们证明，对齐Fn是一个突出的特点，在人类前列腺癌和胰腺癌样本的侵袭部位。总的来说，我们提出了一种新的机制，CAFs组织Fn矩阵，促进定向癌细胞迁移。
Cancer-associated fibroblasts (CAFs) in the tumor stroma play a key role in tumor progression. Erdogan et al. show that CAF-mediated alignment of the fibronectin matrix is a key factor promoting directional cancer cell migration. Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF–cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α–mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.