Adipokines Linking Obesity with Colorectal Cancer Risk in Postmenopausal Women

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cancer Research (Impact Factor: 9.33). 04/2012; 72(12):3029-37. DOI: 10.1158/0008-5472.CAN-11-2771
Source: PubMed


Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.

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    • "n normal and malignant human ovarian surface epithelial cells. Cancer Res (2001) 61:6768–76. 21. Zannoni GF, Monterossi G, De Stefano I, Gargini A, Salerno MG, Farulla I, et al. The expression ratios of estrogen receptor α (ERα) to estrogen receptor β1 (ERβ1) and ERα to ERβ2 identify poor clinical outcome in endometrioid endometrial cancer. Hum Pathol (2013) 44:1047–54. doi:10.1016/j.humpath. 2012.09.007 22. Härkönen PL, Mäkelä SI. Role of estrogens in development of prostate cancer. J Steroid Biochem Mol Biol (2004) 92:297–305. doi:10.1016/j.jsbmb.2004.10.016 23. Siegfried JM. Smoking out reproductive hormone actions in lung cancer. Mol Cancer Res (2014) 12:24–31. doi:10.1158/1541-7786.MCR-13-0580 24. Hogan AM, Collins D, Baird "
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    ABSTRACT: Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERβ is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression ERβ expression is lost, suggesting estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy.
    Frontiers in Oncology 01/2015; 5. DOI:10.3389/fonc.2015.00019
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    • "Epidemiological evidence suggests that circulating plasma concentrations of adiponectin and leptin may not precisely reflect an individual's true or long-term levels [14, 27]. Also, for certain adipokines, the adipokine tissue concentrations in the tumor environment may be more relevant to the assessment of cancer related risk than circulating blood levels. "
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    ABSTRACT: Purpose. The association between obesity and colon neoplasia is well established but the underlying biological mechanisms are not fully understood. Rates of both obesity and colon cancer differ by race. Adipokines have been postulated as contributors to the observed association; however, few studies have examined the mediating effect of adipokines on the obesity-colon adenoma association with consideration of racial differences. Methods. We determined prediagnostic levels of adiponectin and leptin in Caucasians (217 cases and 650 controls) and African Americans (175 cases and 378 controls) participating in the Case Transdisciplinary Research on Energetics and Cancer Colon Adenoma Study. We evaluated mediating effects of adiponectin and leptin on the association of abdominal adiposity and colon adenoma separately according to race using mediational pathway analysis. Results. We observed differences in circulating adipokine concentrations by race; African Americans had higher levels of leptin and lower levels of adiponectin than Caucasians for both adenoma cases and controls (P values <0.001). Leptin and adiponectin did not mediate the waist-to-hip ratio (WHR) adenoma association in either group (all Sobel P values >0.27). Conclusions. We found no evidence that leptin or adiponectin mediates the abdominal obesity-colorectal adenoma pathway. Larger studies on how these associations vary by race, sex, and obesity are needed.
    Journal of Cancer Epidemiology 08/2014; 2014:371254. DOI:10.1155/2014/371254
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    • "Epidemiological data also supported the role of IL-6 and TNF-α in cancer promotion. In a nested case-control study of 1298 postmenopausal women in the United States, Ho GY et al. demonstrated that subjects with IL-6 in highest quartile had a relative risk of 1.41 of developing colorectal cancer though the association was insignificant after adjustment for baseline insulin level[10]. Heikkila K et al. also showed IL-6 was associated with increased lung and breast cancer risks in a meta-analysis of two prospective cohorts, the British Women’s Heart and Health study and the Caerphilly Cohort[11]. In addition, in a sub-group analysis of the Nurses’ Health Study, Chan et al. showed that the relative risk of development colorectal cancer was 1.67(95% CI 1.05-268, p=0.03) in participants with highest quartile of sTNFR-2 level, when compared with those in the lowest quartile[12]. "
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    ABSTRACT: Cytokines released from adipose tissues induce chronic low-grade inflammation, which may enhance cancer development. We investigated whether indices of obesity and circulating adipokine levels could predict incident cancer risk. This longitudinal community-based study included subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS) study commenced in 1995-1996 (CRISP-1) with baseline assessments including indices of obesity. Subjects were reassessed in 2000-2004 (CRISPS-2) with measurement of serum levels of adipokines including interleukin-6 (IL-6), soluble tumor necrosis factor receptor 2 (sTNFR2; as a surrogate marker of tumor necrosis factor-α activity), leptin, lipocalin 2, adiponectin and adipocyte-fatty acid binding protein (A-FABP). Incident cancer cases were identified up to 31 December 2011. 205 of 2893 subjects recruited at CRISPS-1 had developed incident cancers. More of the subjects who developed cancers were obese (22.1 vs 16.1%) or had central obesity (36.6 vs 24.5%) according to Asian cut-offs. Waist circumference (adjusted HR 1.02 [1.00-1.03] per cm; p=0.013), but not body mass index (adjusted HR 1.04 [1.00-1.08] per kg/m(2); p=0.063), was a significant independent predictor for incident cancers after adjustment for age, sex and smoking status. 99 of 1899 subjects reassessed at CRISPS-2 had developed cancers. Subjects who developed cancers had significantly higher level of hsCRP, IL-6, sTNFR2 and lipocalin 2. After adjustment for conventional risk factors, only IL-6 (HR 1.51, 95% CI 1.18-1.95) and sTNFR2 (HR 3.27, 95%CI 1.65-6.47) predicted cancer development. Our data supported the increased risk of malignancy by chronic low grade inflammation related to central obesity.
    PLoS ONE 10/2013; 8(10):e78594. DOI:10.1371/journal.pone.0078594 · 3.23 Impact Factor
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