Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity
Haruki HoriguchiTsuyoshi KadomatsuRyoma KurahashiChiaki HaraKeishi MiyataMasaya BabaHironobu OsumiKazutoyo TeradaKimi ArakiToshiyuki TakaiTomomi KambaW. Marston LinehanToshiro MoroishiYuichi Oike
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Abstract:
Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα + fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8 + T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B–NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.Keywords:
Tumor progression
Angiopoietin 2
Angiopoietin
Angiopoietin 2
Angiopoietin
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Angiopoietin 2
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Aims & Objectives: Sepsis is a life-threatening organ dysfunction caused by dysregulation of host response to infection, and is still a global health problem due to high morbidity and mortality. The pathophysiology of sepsis and septic shock is complex and still not fully understood, but dysregulation of the systemic inflammatory response and endothelial dysfunction is thought to play an important role. One of the biomarkers of endothelial dysfunction is angiopoietin-1 and angiopoietin-2, which in conditions of injury, hypoxia such as in sepsis occurs an imbalance of the Ang-1 and Ang-2. The study aimed to find out the corelation of Angiopoietin and the outcome in pediatric sepsis. Methods: This is an analytical correlational cross sectional study of 83 subjects of sepsis aged 1-18 years in Hasan Sadikin General Hospital during the July-December 2019. Angiopoietin was assesed in all subjects at hospital admission. Statistical analysis using Mann Whitney, and Spearman rank correlation test, with p <0.05 was considered significant. Results: Angiopoietin-1 and angiopoietin-2 are significantly difference between survivor and non survivor group. Angiopoietin-2 was higher in non survivor group (3596 pg/ml vs 2192 pg/ml, p 0,042), and angiopoietin-1 was lower in non survivor group (26,56 pg/ml vs 12,94 pg/ml;p 0,024). Angiopoietin-1, angiopoietin-2, and ang-2/ang-1 ratio are correlated with mortality (r: 0,225, p 0,020; r:0,216,p 0,025; r:0,379, p 0,021). Conclusions: Angiopoietin 2 was higher in non survivor grup, and correlated with hospital mortality.
Angiopoietin 2
Angiopoietin
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Endothelial Dysfunction
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Objective: To detect the expression of angiopoietin-2(Ang-2)in placentas,and to evaluate the role of Ang-2 in FGR.Methods: Immunohistochemistry(SP) was used to investigate the distribution and location of angiopoietin-2 and the semi-quantitative method of reverse transcription polymerase chain reaction(RT-PCR) was employed to investigate the mRNA expression levels of angiopoietin-2 in placenta tissues of normal pregnant women and women with FGR.Results:1.S-P:(1)Ang-2 was located in trophoblast,endothelial cells and paravascular cells of placentas.(2)The mean density of angiopoietin-2 in group of FGR was significantly lower than that in normal group(P0.05).2.RT-PCR: Compared with the normal group,the mRNA expression levels of angiopoietin-2 was reduced(P0.05).Conclusion: The expression of Ang-2 was greatly reduced in late pregnancy,It maybe play an important role in the pathogenic causes of preeclampsia.
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The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined angiopoietin-1 and angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced angiopoietin-1 and increased angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.
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Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) play critical roles in angiogenesis in hepatocellular carcinoma (HCC). In addition, recent data suggest that Ang-1/Ang-2 are involved in regulating the immune response. The aim of our study was to explore the clinical prognostic significance of plasma Ang-1 and Ang-2 in HCC. We prospectively enrolled and collected data and blood samples from 767 HCC patients treated at MD Anderson Cancer Center between 2001 and 2014. Controls consisted of cirrhotic patients (n = 75) and healthy volunteers (n = 200). The cutoff value was the median level of each angiogenic factor. Overall survival (OS) was estimated by Kaplan-Meier curves and compared by the log-rank test. Higher plasma Ang-2 was significantly associated with advanced clinicopathologic features of advanced HCC and lower OS. Median OS was 61.8 months (95% confidence interval [CI], 45.1-78.5 months) for low Ang-2 compared with 28.5 months (95% CI, 24.8-32.1 months) for high Ang-2 (p < 0.001). In contrast, higher Ang-1 was associated with longer OS. Median OS was 37.2 months (95% CI, 31.0-43.4 months) for high Ang-1 compared with 26.2 months (95% CI, 22.2-30.3 months) for those with low Ang-1 (p = 0.043). In conclusion, our findings indicate that plasma Ang-1 and Ang-2 levels are potential diagnostic and prognostic biomarkers in HCC.
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Angiogenesis is important in the promotion and progression of malignancy. The formation of new blood vessels is coordinated by many factors, angiopoietins among others. Overexpression of angiopoietins has been observed in various tumors. The aim of the study was to evaluate plasma concentration of Ang-1, Ang-2 and Tie-2 in cervical cancer.The study group consisted of 34 patients with cervical cancer and the control group of 20 healthy volunteers. Plasma concentrations of Ang-1, Ang-2 and Tie-2 were evaluated by ELISA.Plasma concentrations of Ang-1, Ang-2, Tie-2 and Ang-1/Ang-2 ratios were significantly higher in cervical cancer patients than in controls. Although there was no correlation between concentration of Ang-1, Ang-2, Tie-2 and clinical stage (FIGO), the Ang-1/Ang-2 ratio was higher in Stage I than in II-III. Ang-1 correlated positively with Ang-2 and Tie-2 in a subgroup with Stage II-III and Ang-2 with Tie-2 in a subgroup with Stage I.Plasma concentrations of Ang- 1, Ang-2 and Tie-2 may be useful additional tumor markers in cervical cancer.
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