IFNγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of Dll4

Jingjing Deng; Xiaoman Liu; Lijie Rong; Chen Ni; Xiao Li; Wei Yang; Yu Lu; Xiyun Yan; Chuan Qin; Lianfeng Zhang; Zhihai Qin

doi:10.1002/path.4340

IFNγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of Dll4

J Pathol. 2014 Jun;233(2):170-82. doi: 10.1002/path.4340. Epub 2014 Mar 28.

Authors

Jingjing Deng¹, Xiaoman Liu, Lijie Rong, Chen Ni, Xiao Li, Wei Yang, Yu Lu, Xiyun Yan, Chuan Qin, Lianfeng Zhang, Zhihai Qin

Affiliation

¹ 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.

PMID: 24615277
DOI: 10.1002/path.4340

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.

Keywords: Dll4; IFNγ; IFNγR; angiostasis; delta-like ligand 4; endothelium; notch pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Calcium-Binding Proteins
Cell Line, Tumor
Down-Regulation
Endothelial Cells / metabolism*
Endothelial Cells / pathology
Gene Expression Regulation, Neoplastic
Human Umbilical Vein Endothelial Cells / metabolism
Human Umbilical Vein Endothelial Cells / pathology
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Interferon gamma Receptor
Interferon-gamma / metabolism*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, SCID
Mice, Transgenic
Neoplasms / blood supply*
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology
Neovascularization, Pathologic*
Pericytes / metabolism
Pericytes / pathology
Promoter Regions, Genetic
Receptor, TIE-2 / genetics
Receptors, Interferon / genetics
Receptors, Interferon / metabolism
Signal Transduction
Time Factors
Transfection
Tumor Burden

Substances

Adaptor Proteins, Signal Transducing
Calcium-Binding Proteins
DLL4 protein, human
DLL4 protein, mouse
IFNG protein, human
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Receptors, Interferon
Interferon-gamma
Receptor, TIE-2