TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
2014 (English)In: Nature Communications, ISSN 2041-1723, Vol. 5, no 4944Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
Nature Publishing Group: Nature Communications , 2014. Vol. 5, no 4944
IdentifiersURN: urn:nbn:se:liu:diva-120670DOI: 10.1038/ncomms5944ISI: 000358590800001PubMedID: 25229256OAI: oai:DiVA.org:liu-120670DiVA: diva2:847525
Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute; Torsten Soderbergs foundation; Soderbergs stiftelse; Tianjin Natural Science Foundation (CMM-Tianjin) [09ZCZDSF04400]; European Union ; European Research Council (ERC) advanced grant ANGIOFAT 2015-08-202015-08-202015-08-25