IFNγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of DII4

Although IFN is regarded as a key cytokine in angiostatic response, our poor understanding of its effective cellular target drastically limits its clinical trials against angiogenesis-related disorders. Here, we investigated the effect of IFN on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2(IFNR) mice, in which IFNR expression was reconstituted under the control of Tie2 promoter in IFNR-deficient mice, we found that the response of ECs to IFN was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNR on Tie2(-) cells did not inhibit, but promoted tumour growth in control wild-type mice. Mechanism studies showed that IFN reacting on ECs down-regulated the delta-like ligand 4 (Dll4)/Notch signalling pathway. Accordingly, overexpression of Dll4 in human ECs diminished the effect of IFN on ECs. This study demonstrates that the action of IFN on ECs, but not other cells, is highly effective for tumour angiostasis, which involves down-regulating Dll4. It provides insights for EC-targeted angiostatic therapy in treating angiogenesis-associated disorders in the clinic. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.