title: IFNγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of Dll4.
abstract: Although IFNγ 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 IFNγ on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2(IFNγR) mice, in which IFNγR expression was reconstituted under the control of Tie2 promoter in IFNγR-deficient mice, we found that the response of ECs to IFNγ was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNγR on Tie2(-) cells did not inhibit, but promoted tumour growth in control wild-type mice. Mechanism studies showed that IFNγ 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 IFNγ on ECs. This study demonstrates that the action of IFNγ 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.
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Deng
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Liu
authors.forename: Lijie
authors.initials: L
authors.lastname: Rong
authors.forename: Chen
authors.initials: C
authors.lastname: Ni
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiyun
authors.initials: X
authors.lastname: Yan
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000096743:Interferon gamma Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D042787:Receptor, TIE-2; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; C573415:IFNG protein, human
keywords: Dll4; IFNγ; IFNγR; angiostasis; delta-like ligand 4; endothelium; notch pathway