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The indirect antiangiogenic effect of IL‐37 in the tumor microenvironment
Author(s) -
Mei Yu,
Zhu Ying,
Teo Huey Yee,
Liu Yonghao,
Song Yuan,
Lim Hwee Ying,
Binte Hanafi Zuhairah,
Angeli Veronique,
Liu Haiyan
Publication year - 2020
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3ma0220-207rr
Subject(s) - angiogenesis , cancer research , biology , cytokine , neovascularization , tumor microenvironment , mmp9 , in vivo , matrix metalloproteinase , endothelial stem cell , carcinogenesis , immunology , microbiology and biotechnology , in vitro , downregulation and upregulation , cancer , biochemistry , genetics , tumor cells , gene
IL‐37, a newly identified IL‐1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL‐37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL‐37 promoted angiogenesis through TGF‐β signaling in both physiologic and pathologic conditions. Therefore, the function of IL‐37 in tumoral angiogenesis is not clear and the underlying mechanism is not known. In this current study, we investigated the direct role of IL‐37 on endothelial cells, as well as its indirect effect on angiogenesis through functioning on tumor cells both in vitro and in vivo. We found that IL‐37 treatment directly promoted HUVEC migration and tubule formation, indicating IL‐37 as a proangiogenic factor. Surprisingly, the supernatants from IL‐37 overexpressing tumor cell line promoted HUVEC apoptosis and inhibited its migration and tubule formation. Furthermore, we demonstrated that IL‐37 suppressed tumor angiogenesis in a murine orthotopic hepatocellular carcinoma model, suggesting its dominant antiangiogenesis role in vivo. Moreover, microarray and qPCR analysis demonstrated that IL‐37 reduced the expressions of proangiogenic factors and increased the expressions of antiangiogenic factors by tumor cells. Matrix metalloproteinase (MMP)2 expression was significantly decreased by IL‐37 in both cell lines and murine tumor models. MMP9 and vascular endothelial growth factor expressions were also reduced in murine tumors overexpressing IL‐37, as well as in cell lines overexpressing IL‐37 under hypoxic conditions. In conclusion, although IL‐37 could exert direct proangiogenic effects on endothelial cells, it plays an antiangiogenic role via modulating proangiogenic and antiangiogenic factor expressions by tumor cells in the tumor microenvironment.