| First Author | Deng J | Year | 2014 |
| Journal | J Pathol | Volume | 233 |
| Issue | 2 | Pages | 170-82 |
| PubMed ID | 24615277 | Mgi Jnum | J:210990 |
| Mgi Id | MGI:5573002 | Doi | 10.1002/path.4340 |
| Citation | Deng J, et al. (2014) IFNgamma-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of Dll4. J Pathol 233(2):170-82 |
| abstractText | Although IFNgamma 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 IFNgamma on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2(IFNgammaR) mice, in which IFNgammaR expression was reconstituted under the control of Tie2 promoter in IFNgammaR-deficient mice, we found that the response of ECs to IFNgamma was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNgammaR on Tie2(-) cells did not inhibit, but promoted tumour growth in control wild-type mice. Mechanism studies showed that IFNgamma 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 IFNgamma on ECs. This study demonstrates that the action of IFNgamma 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. |
