NF-κB signaling in endothelial cells Identification of NIK as a therapeutic target

Angiogenesis is a major contributor to disease progression in several pathologies including chronic inflammatory disease and cancer. Inflammation is a key factor that drives pathological angiogenesis and signaling through conduits such as the canonical NF-kappaB pathway in endothelial cells have been well established to contribute to this. However, the role of the noncanonical NF-kappaB pathway and its main regulator NF-kappaB inducing kinase (NIK) in these processes was hitherto largely unknown. This thesis delves deeper into the importance of NIK in the regulation of pathological angiogenesis in the context of rheumatoid arthritis (RA), atherosclerosis and colorectal cancer by using novel multicellular in vitro culture models, patient cohorts and various molecular tools modulating the expression of components of the NF-kappaB signaling pathways. Through these studies we have established NIK as a central mediator of lymphotoxin beta receptor (LTβR)-induced synovial neovascularization associated with RA, inflammatory and adverse plaque phenotypes in atherosclerosis, and alternative angiogenic pathways linked to metastatic colorectal cancer. Additionally, it was demonstrated that crosstalk between NIK and canonical NF-kappaB signaling is important for a sustained inflammatory response by endothelial cells. Furthermore, blockade of NIK either by siRNA or a pharmacological NIK inhibitor abrogated neovascularization and inflammatory responses in endothelial cells. Therefore, NIK may be a potential therapeutic target in diseases such as RA, atherosclerosis and (colorectal) cancer.