TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.
TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.
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DOI：
10.1038/onc.2015.133
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发表时间：
2016-02-11
期刊：
影响因子：
8
通讯作者：
Fuxe J
中科院分区：
文献类型：
--
作者：
Pang MF;Georgoudaki AM;Lambut L;Johansson J;Tabor V;Hagikura K;Jin Y;Jansson M;Alexander JS;Nelson CM;Jakobsson L;Betsholtz C;Sund M;Karlsson MC;Fuxe J
在乳腺癌和许多其他类型的癌症的转移性扩散过程中，肿瘤细胞经常通过淋巴系统扩散。然而，目前尚不清楚肿瘤细胞如何进入淋巴系统，以及它们如何选择淋巴管和血管进行迁移。在这里，我们报告说，经历上皮间质转化（EMT）的乳腺肿瘤细胞响应转化生长因子-β（TGF-β1）而被激活，通过淋巴系统进行靶向迁移，类似于炎症期间的树突状细胞（DC）。在体内和 3D 培养中，与血管相比，EMT 细胞优先向淋巴管迁移。这种靶向迁移的机制可追溯到 TGF-β1 促进 CCR7/CCL21 介导的肿瘤细胞和淋巴管内皮细胞之间串扰的能力。一方面，TGF-β1通过p38 MAP激酶介导的JunB转录因子的激活促进EMT细胞中CCR7的表达。阻断 CCR7 或使用 p38 MAP 激酶抑制剂治疗，可减少同系小鼠中 EMT 细胞的淋巴传播。另一方面，TGF-β1促进淋巴内皮细胞中CCL21的表达。 CCL21 以旁分泌方式介导 EMT 细胞向淋巴管内皮细胞的趋化迁移。结果确定了 TGF-β1 诱导的 EMT 机制，可激活肿瘤细胞通过淋巴系统进行有针对性的 DC 样迁移。此外，这表明 p38 MAP 激酶抑制可能是抑制肿瘤细胞 EMT 和淋巴扩散的有效策略。
Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial–mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.