title: TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, No.105, Jiefang Road, Jinan, Shandong 250013, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen 2200N, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Dissing
authors.affiliation: Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210009, China.
authors.forename: Xia
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1] Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden [2] Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden [3] Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3