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NF‐κB ‐inducing kinase is a key regulator of inflammation‐induced and tumour‐associated angiogenesis
Author(s) -
Noort Ae R,
van Zoest Katinka PM,
Weijers Ester M,
Koolwijk Pieter,
Maracle Chrissta X,
Novack Deborah V,
Siemerink Martin J,
Schlingemann Reinier O,
Tak Paul P,
Tas Sander W
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4403
Subject(s) - angiogenesis , inflammation , cancer research , chemokine , vascular endothelial growth factor , nf κb , neovascularization , arthritis , medicine , immunology , kinase , metastasis , regulator , iκb kinase , biology , cancer , microbiology and biotechnology , vegf receptors , biochemistry , gene
Angiogenesis is essential during development and in pathological conditions such as chronic inflammation and cancer progression. Inhibition of angiogenesis by targeting vascular endothelial growth factor ( VEGF ) blocks disease progression, but most patients eventually develop resistance which may result from compensatory signalling pathways. In endothelial cells ( ECs ), expression of the pro‐angiogenic chemokine CXCL12 is regulated by non‐canonical nuclear factor ( NF )‐ κB signalling. Here, we report that NF‐κB ‐inducing kinase ( NIK ) and subsequent non‐canonical NF‐κB signalling regulate both inflammation‐induced and tumour‐associated angiogenesis. NIK is highly expressed in endothelial cells ( ECs ) in tumour tissues and inflamed rheumatoid arthritis synovial tissue. Furthermore, non‐canonical NF‐κB signalling in human microvascular ECs significantly enhanced vascular tube formation, which was completely blocked by siRNA targeting NIK . Interestingly, Nik −/− mice exhibited normal angiogenesis during development and unaltered TNFα ‐ or VEGF ‐induced angiogenic responses, whereas angiogenesis induced by non‐canonical NF‐κB stimuli was significantly reduced. In addition, angiogenesis in experimental arthritis and a murine tumour model was severely impaired in these mice. These studies provide evidence for a role of non‐canonical NF ‐κ B signalling in pathological angiogenesis, and identify NIK as a potential therapeutic target in chronic inflammatory diseases and tumour neoangiogenesis. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.