Leptin and Soluble Leptin Receptor in Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition Cohort

Abstract

Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P trend ¼ 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P trend ¼ 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P trend ¼ 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P trend ¼ 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. Cancer Res; 72(20); 5328-37. Ó2012 AACR.

Obesity Biomarkers, Metabolism and Risk of Cancer: An Epidemiological Perspective

“…In a prospective study from Sweden, higher circulating leptin was associated with higher risk of colon cancer in men but not in women [71]. Similarly, in EPIC pre-diagnostic leptin was associated with higher colon cancer risk only in men, while in women no association was observed [72]. A positive positive association between pre-diagnostic circulating leptin concentrations and risk of colon cancer in men was also observed in a study from Norway [73].…”

“…In a meta-analysis including six prospective studies, higher leptin concentrations were significantly associated with higher risk of colorectal cancer [76]. Interestingly, soluble leptin receptor (sOB-R), which determines the bioactivity of leptin, was strongly inversely associated with risk of colorectal cancer in EPIC [72]. In two US cohorts soluble leptin receptor was not associated with higher overall colorectal cancer risk in either men or women, although high sOB-R concentrations were associated with higher rectal cancer risk in women [56].…”

Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development

“…The level of leptin or ObRb has been found to be associated with an increased risk of CRC, although some study revealed a normal level of leptin in the serum of patients with CRC (Aleksandrova et al, 2012;Aloulou et al, 2008). A recent study (with 3,614 CRC vs 1,215 CRA vs 5,220 controls) found a positive association between serum leptin and the CRA risk, but not with the CRC risk (Gialamas et al, 2013).…”

“…A growing body of evidence indicates that the metabolic syndrome (MetS) and expression of various adipokines (leptin and adiponectin) associated with obesity plays a crucial role in the development of colorectal cancer (Hardwick et al, 2001;Hoda et al, 2007;Endo et al, 2011;Aleksandrova et al, 2012;Healy et al, 2012;Erkasap et al, 2013;Gialamas et al, 2013). In obese people, the elevated insulin level, the rapidly growing secretion of leptin, and decreased adiponectin levels altogether activate several signaling pathways that favor carcinogenesis and are associated with colon cancer development.…”

“…In the indirect pathway, adiponectin acts through mediators such as insulin and proinflammatory factors. Indeed, a recent study suggests that altered adiponectin levels are engaged in energy imbalance and insulin resisance and have a pro-inflamatory effect (Hotamisligil, 2006;Mattar et al, 2011;Aleksandrova et al, 2012;Landskron et al, 2014;Mariani et al, 2014). Direct involvement of adiponectin in carcinogenesis is through action on cancer cells by contribution to cell proliferation and to the process of tissue remodeling (Tae et al, 2014).…”