Serum adiponectin levels and tissue expression of adiponectin receptors are associated with risk, stage, and grade of colorectal cancer

Abstract

Adiponectin has been associated with colorectal cancer (CRC) risk. This study aims to investigate the association of both adiponectin and tissue expression of its receptors with CRC risk as well as clinicopathological characteristics, notably stage and grade. Determination of serum adiponectin and immunohistochemical expression of adiponectin receptors in adenocarcinoma/normal colorectal tissue was performed in samples from 104 newly diagnosed CRC patients and 208 age- and sex-matched controls. Multiple logistic regression odds ratios and 95% confidence intervals for CRC risk were derived, controlling for a series of covariates. Serum adiponectin was negatively associated with CRC risk (odds ratio, 0.72; confidence interval, 0.53-0.99) and also with tumor grade (P = .05). Expression of both adiponectin receptors was stronger in adenocarcinoma vs normal tissue (P = .001). AdipoR1 expression was negatively associated with nodal stage (P = .03); AdipoR2 expression was positively associated with tumor, node, metastasis stage (P = .01). Established positive associations with red meat consumption and diabetes, and negative associations with physical exercise and plant food consumption were confirmed along with a more than 60% higher risk associated with central obesity. Adiponectin levels and tissue expression of hormonal receptors seem to be associated not only with CRC risk but also with components of clinicopathological characteristics; given power limitations, these results should be interpreted with caution. The exact nature of the association and the underlying pathophysiological mechanisms need to be further examined in large prospective studies assessing adiponectin and its receptors as novel targets for exploring CRC growth.

Introduction

Obesity, especially abdominal fat accumulation, leads to metabolic inequilibrium, adipose tissue dysfunction, and insulin resistance [1]. Body mass index (BMI), an index of total obesity, and waist to hip ratio (WHR), an index of central obesity, are positively associated with several malignancies, including colorectal cancer (CRC) [2], [3], [4], [5], [6], [7], [8]. It has been also recently shown that obesity is related with inflammation in the colorectal mucosa, whereas diet-induced weight loss reduces this inflammatory state, thereby potentially lowering CRC risk [9].

Adiponectin, a 30-kd complement C1q-related protein, is exclusively produced by adipocytes [10]; and its actions are mediated by binding and activating specific adiponectin receptors, AdipoR1 and AdipoR2 [11]. Insulin-sensitizing effects have been attributed to adiponectin [11]; in contrast to other adipokines, such as leptin, however, the circulating levels of this hormone are decreased in obese individuals [1], [4]. Low adiponectin levels and insulin resistance have been linked to several obesity-related disease entities, such as type 2 diabetes mellitus, hypertension, and atherosclerosis [1], [4], [11], [12]. Adiponectin has also been proposed as a biological link between obesity and several malignancies, including CRC [4], [13], [14], [15], [16]. Specifically, adiponectin levels are lower in CRC patients; and its receptors, expressed in both adenocarcinoma and normal colorectal tissue, may mediate its effects on cellular proliferation and apoptosis [17], [18], [19], [20]. The above observations suggest that adiponectin may act directly on CRC cells and/or indirectly by regulating whole-body insulin sensitivity [13].

Adiponectin has been reported to be negatively associated with prostate [21], [22], endometrial [23], renal cancer [14] grade and lung cancer stage [24], suggesting its possible involvement in cancer progression. There is paucity of data, however, regarding the relation of the hormone and its receptors with a common type of cancer, namely, CRC, and the clinicopathological implications. Specifically, a correlation of low adiponectin levels with increasing stage of nonmetastatic CRC has been reported in one study [25] and a negative correlation with CRC stage in another [26], but no statistically significant difference of adiponectin levels between early and metastatic stage of CRC was confirmed [27]. An inverse relation of AdipoR1 and AdipoR2 expression levels with unfavorable T stage and grade of CRC has been found [17]. Additionally, higher expression of both adiponectin receptors in adenocarcinoma compared with normal colorectal tissue has been noted [28], not confirmed, however, by Yoneda et al. [20]. No prior study has simultaneously evaluated circulating adiponectin and expression of its receptors in relation to CRC risk and clinicopathological characteristics, in both cases and controls, controlling for known confounding factors.

We have conducted a case-control study comprising 104 CRC patients and 208 age- and sex-matched controls, aiming to simultaneously explore the association of serum adiponectin levels and expression of adiponectin receptors with CRC risk and clinicopathological characteristics, notably tumor grade, stage, metastatic status, tumor location, and size.