1] Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden [2] Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210009, China.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Nat Commun. 2014 Sep 17;5:4944. doi: 10.1038/ncomms5944.
Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-α markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-α-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-α-induced lymphangiogenesis. Moreover, TNF-α-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-α-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-α-TNFR1 pathway.
炎症和淋巴管生成是两个紧密偶联的过程，促进肿瘤生长和侵袭。在这里，我们报告 TNF-α 显著促进肿瘤淋巴管生成和淋巴转移。TNF-α-TNFR1 信号通路通过 VEGFR3 非依赖性机制直接刺激淋巴管内皮细胞活性。然而，VEGFR3 诱导的淋巴管内皮细胞尖端是体内淋巴管生长的前提条件，VEGFR3 阻断完全消除 TNF-α 诱导的淋巴管生成。此外，TNF-α-TNFR1 激活的炎症巨噬细胞产生高水平的 VEGF-C，以协调激活 VEGFR3。在小鼠中敲除 TNFR1（Tnfr1(-/-)）或耗尽肿瘤相关巨噬细胞（TAMs）几乎消除了 TNF-α 诱导的淋巴管生成和淋巴转移。功能获得实验表明，在 Tnfr1(-/-)小鼠中重建 Tnfr1(+/+)巨噬细胞在很大程度上恢复了肿瘤淋巴管生成和淋巴转移。这些发现揭示了炎症和淋巴管生成在癌症转移中的密切相互作用的机制，并提出通过靶向 TNF-α-TNFR1 途径来治疗淋巴转移。
