Format

Send to

Choose Destination
Nat Commun. 2014 Sep 17;5:4944. doi: 10.1038/ncomms5944.

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.

Author information

1
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.
2
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
3
Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, No.105, Jiefang Road, Jinan, Shandong 250013, China.
4
Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen 2200N, Denmark.
5
Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210009, China.
6
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.

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.

PMID:
25229256
DOI:
10.1038/ncomms5944
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for Linkoping University Electronic Press
Loading ...
Support Center