Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer

Wang, Weiqiang; Zhao, Dan; Zhou, Yushan; Hu, Xiaoyu; Sun, Zhina; Yu, Gang; Wu, Wantong; Chen, Song; Kuang, Jiu-long; Xu, Guogang; Han, Zhong Chao; Wang, Bangmao; Yang, Jingxian; Feng, Xiaoming

doi:10.1038/aps.2015.3

Cited by 23 publications

(26 citation statements)

References 26 publications

(28 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro studies further proved that rhIL‐37 directly promote CD4 + T‐cell proliferation. These results suggested an antitumor role of IL‐37 in breast cancer, probably through activating T‐cell responses …”

Section: Il‐37 In Tumormentioning

confidence: 79%

“…It would be interesting to investigate the IL‐1R8 expressions in various cancer types as downregulation of IL‐1R8 expression might serve as another possible mechanism for cancer cells to evade the IL‐37–mediated antitumor activity. Although IL‐37 could directly inhibit tumor cell growth, this direct inhibition was diminished in immune‐incompetent nude and SCID mice in murine fibrosarcoma and breast cancer models . These findings may lead to an unexpected fact that the in vitro direct effect of IL‐37 on tumor cell growth may not be sufficient for its antitumor role in vivo.…”

Section: Mechanisms Involved In Il‐37 Antitumor Effects and Future Pementioning

confidence: 99%

“…In murine subcutaneous HCC model, IL‐37 could facilitate the recruitment of NK cells to the tumor site . In murine breast cancer model, the antitumor activity of IL‐37 was abrogated in nude and SCID mice . Although the evidence is still quite limited, IL‐37 could exert its antitumor function through promoting antitumor immune response.…”

Section: Mechanisms Involved In Il‐37 Antitumor Effects and Future Pementioning

confidence: 99%

“…Although IL-37 could directly inhibit tumor cell growth, this direct inhibition was diminished in immuneincompetent nude and SCID mice in murine fibrosarcoma and breast cancer models. 48,50 These findings may lead to an unexpected fact that the in vitro direct effect of IL-37 on tumor cell growth may not be sufficient for its antitumor role in vivo.…”

Section: Il-37 Treatment Could Significantly Reduce Tumor Cell Viabilmentioning

confidence: 99%

See 3 more Smart Citations

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Liu

2018

Cancer Reports

View full text Add to dashboard Cite

Background IL‐37 is a newly identified IL‐1 family cytokine. Unlike other members in IL‐1 family, IL‐37 has been demonstrated to be an anti‐inflammatory cytokine in many inflammatory and autoimmune diseases. IL‐37 is regarded as a dual‐function cytokine as both the extracellular and intracellular IL‐37 are biologically functional. Extracellular IL‐37 can bind to IL‐18Rα and IL‐1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL‐37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL‐37 in tumor development has been extensively studied. Recent findings IL‐37 has been found to play an antitumor role in various types of tumors, such as non‐small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL‐37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL‐37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti‐inflammatory function. We focused on the role of IL‐37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. Conclusion IL‐37 may affect tumor development through multiple mechanisms: (1) IL‐37 directly influences tumor cell viability; (2) IL‐37 regulates the immune response to promote the antitumor immunity; and (3) IL‐37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL‐37 in animal models and cancer patients.

show abstract

Section: Il‐37 In Tumormentioning

confidence: 79%

Section: Mechanisms Involved In Il‐37 Antitumor Effects and Future Pementioning

confidence: 99%

Section: Mechanisms Involved In Il‐37 Antitumor Effects and Future Pementioning

confidence: 99%

Section: Il-37 Treatment Could Significantly Reduce Tumor Cell Viabilmentioning

confidence: 99%

See 2 more Smart Citations

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Liu

2018

Cancer Reports

View full text Add to dashboard Cite

show abstract

“…IL‐37 has been identified as a natural suppressor of innate inflammatory and immune responses 8, 12. Recent studies have indicated that IL‐37 plays a protective role in tumor progression in mouse fibrosarcoma,9 human lung cancer,14, 42 hepatocellular carcinoma,13 breast cancer,43 cervical cancer,44 and renal cell carcinoma 45. Zhang et al15 found that IL‐37 inhibits colon cancer progression via β‐catenin suppression and that a lack of IL‐37 is associated with poor survival.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

et al. 2018

View full text Add to dashboard Cite

Interleukin (IL)‐37 and neutrophils are considered to be involved in human cancer, but their prognostic significance in colorectal cancer (CRC) has not been elucidated. The aim of this study was to evaluate the prognostic value of IL‐37 expression and neutrophil levels in CRC. We retrospectively analyzed IL‐37 expression, CD66b+ neutrophil levels, and mismatch repair (MMR) status in 337 paraffin‐embedded CRC specimens from the training cohort by immunohistochemistry. Their prognostic values were assessed using Kaplan‐Meier curves and multivariate Cox regression models. Moreover, several risk factors were used to form nomograms to evaluate survival, and the performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. Further validation was performed in an independent cohort of 245 cases. Low IL‐37 expression and high CD66b+ neutrophil levels were significantly associated with diminished disease‐free survival (DFS) and overall survival (OS), and patients with MMR‐deficient CRC had better clinical outcomes. Furthermore, multivariate Cox analysis identified IL‐37, CD66b+ neutrophils, and MMR status as independent prognostic factors for DFS and OS. Two nomograms integrating the three markers with four clinicopathological risk factors were developed and validated for predicting DFS and OS with good calibration and discrimination (C‐index: training cohort, 0.798 (95% confidence interval:0.764‐0.832) and 0.828 (0.796‐0.860), respectively; validation cohort, 0.739 (0.696‐0.783) and 0.761 (0.715‐0.808), respectively). Decision curve analysis demonstrated that the nomograms were clinically useful. Intratumoral IL‐37, CD66b+ neutrophils, and MMR status were independent prognostic factors for CRC patients. Nomograms incorporating these biomarkers and clinicopathological features could be conveniently used to facilitate the individualized prediction of DFS and OS.

show abstract

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Zhu

Teo

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

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-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.

show abstract

Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer

Abstract: IL-37b exerts anti-4T1 breast carcinoma effects in vivo by modulating the tumor microenvironment and influencing T cell activation.

Cited by 23 publications

References 26 publications

IL‐37: An anti‐inflammatory cytokine with antitumor functions

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Contact Info

Product

Resources

About