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A prospective study of circulating C-reactive protein, interleukin-6, and tumor necrosis factor ? receptor 2 levels and risk of ovarian cancer.

ABSTRACT: Chronic inflammation may play a role in ovarian carcinogenesis. We examined associations between 3 plasma biomarkers of inflammation-C-reactive protein (CRP), interleukin 6, and tumor necrosis factor ? receptor 2-and risk of invasive epithelial ovarian cancer in prospectively collected samples from the Nurses' Health Study (NHS; 1989-2010), Nurses' Health Study II (NHS II; 1996-2009), and the Women's Health Study (WHS; 1992-2011) and performed a meta-analysis including data from previous publications. Associations with ovarian cancer risk were calculated using logistic regression (NHS/NHS II; n = 217 cases) or Cox proportional hazards regression (WHS; n = 159 cases). Study-specific results were combined using random-effects meta-analysis. In the NHS/NHS II and WHS, we observed a 53% increased risk of invasive ovarian cancer when comparing women in the fourth quartile of CRP with women in the first quartile (95% confidence interval (CI): 1.05, 2.23). A CRP level of >10 mg/L versus a level of ?1 mg/L was associated with a 2.16-fold increased risk (95% CI: 1.23, 3.78). In a meta-analysis of published studies, women in the third tertile of CRP had a 35% increased risk (95% CI: 1.10, 1.67) compared with women in the first tertile. There were no significant associations between interleukin 6 or tumor necrosis factor ? receptor 2 and risk in the NHS/NHS II. Our results support the hypothesis that higher levels of circulating CRP are associated with increased risk of ovarian cancer, indicating that the role of inflammation in ovarian cancer requires further elucidation.

SUBMITTER: Poole EM

PROVIDER: S-EPMC3792725 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A prospective study of circulating C-reactive protein, interleukin-6, and tumor necrosis factor α receptor 2 levels and risk of ovarian cancer.

Poole Elizabeth M EM Lee I-Min IM Ridker Paul M PM Buring Julie E JE Hankinson Susan E SE Tworoger Shelley S SS

American journal of epidemiology 20130821 8

Chronic inflammation may play a role in ovarian carcinogenesis. We examined associations between 3 plasma biomarkers of inflammation-C-reactive protein (CRP), interleukin 6, and tumor necrosis factor α receptor 2-and risk of invasive epithelial ovarian cancer in prospectively collected samples from the Nurses' Health Study (NHS; 1989-2010), Nurses' Health Study II (NHS II; 1996-2009), and the Women's Health Study (WHS; 1992-2011) and performed a meta-analysis including data from previous publica ...[more]

PMID: 23966559

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Project description:Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs.Ascites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-?, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48?h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2- Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC.High levels of immunosuppressive (sTNFR2, IL-10, and TGF-?) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-?) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets.IL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs.

Project description:IntroductionLarge-scale clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration.MethodsPatients with type 2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels ≥ 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month 4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses.ResultsParticipants (n = 123) had a mean age of 64.1 years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m2 (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2 mg/gCr (IQR 7.1-48.7) to 13.3 mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102, p < 0.05).ConclusionAfter the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM.Trial registration numberUMIN000031947.

Dataset Information

A prospective study of circulating C-reactive protein, interleukin-6, and tumor necrosis factor ? receptor 2 levels and risk of ovarian cancer.

Publications

A prospective study of circulating C-reactive protein, interleukin-6, and tumor necrosis factor α receptor 2 levels and risk of ovarian cancer.

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