TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
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DOI：
10.1038/ncomms5944
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发表时间：
2014-09-01
影响因子：
16.6
通讯作者：
Cao, Yihai
中科院分区：
文献类型：
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作者：
Ji, Hong;Cao, Renhai;Cao, Yihai
炎症和淋巴管生成是促进肿瘤生长和侵袭的两个内聚耦合过程。在这里，我们报告，TNF-α显着促进肿瘤淋巴管生成和淋巴转移。TNF-α-TNFR 1信号通路通过VEGFR 3非依赖性机制直接刺激淋巴管内皮细胞活性。然而，VEGFR 3诱导的淋巴管内皮细胞尖端是体内淋巴管生长的先决条件，并且VEGFR 3阻断完全消除TNF-α诱导的淋巴管生成。此外，TNF-α-TNFR 1激活的炎性巨噬细胞产生高水平的VEGF-C以协同激活VEGFR 3。在小鼠中TNFR 1（Tnfr 1（-/-））的基因缺失或肿瘤相关巨噬细胞（TAM）的耗竭实际上消除了TNF-α诱导的淋巴管生成和淋巴转移。功能获得实验表明，Tnfr 1（+/+）小鼠中Tnfr 1（+/+）巨噬细胞的重建在很大程度上恢复了肿瘤淋巴管生成和淋巴转移。这些发现揭示了癌症转移中炎症和淋巴管生成之间的密切相互作用的机制，并提出了通过靶向TNF-α-TNFR 1途径对淋巴转移进行治疗性干预。
Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-alpha markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-alpha-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-alpha-induced lymphangiogenesis. Moreover, TNF-alpha-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1(-/-)) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-alpha-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1(+/+) macrophages in Tnfr1(+/+) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-alpha-TNFR1 pathway.