Serum adiponectin levels and tissue expression of adiponectin receptors are associated with risk, stage, and grade of colorectal cancer
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.
Section snippets
Methods
During a 5-year period (2002-2007), 104 histologically confirmed, incident cases of CRC, diagnosed according to C18, C19, and C20 codes of the International Classification of Diseases, 10th Revision [29], in 6 hospitals in Athens, Greece, were recruited in the study. Study subjects had received no prior cancer treatment and had never been diagnosed with any other type of cancer, familial adenomatous polyposis, or inflammatory bowel disease.
Surgically resected cancer specimens were
Results
Data concerning demographic, anthropometric, and lifestyle variables; diabetes mellitus status; and adiponectin levels for the 104 CRC patients and 208 age- and sex-matched controls are shown in Table 1. Men comprised 62.5% of the matched data set; and the mean age was 69.8 and 69.1 years among cases and controls, respectively. These data serve mostly descriptive purposes and are not directly interpretable because of mutual confounding. They confirm, however, the established positive
Discussion
The present case-control study confirms the inverse association of serum adiponectin levels with CRC risk and, for the first time, shows an additional inverse association with advanced tumor grade. Immunohistochemically, the stronger expression of both AdipoR1 and AdipoR2 receptors was also confirmed in adenocarcinoma compared with normal colorectal tissue adjacent to the tumor of the same individuals. Moreover, an inverse association of AdipoR1 expression with regional lymph node metastasis (N
Conflicts of interest
None to declare.
Acknowledgment
We thank Dr. D Korkolis; Vicky Kalampoki and Nick Dessypris, statisticians; as well as M Flessa, health visitor, for their valuable contribution to the study. Funding: The project was supported in part by the Medical School, National and Kapodistrian University of Athens, Greece; Beth Israel Deaconess Medical Center; and grant DK81913 from the National Institute of Diabetes and Digestive and Kidney Diseases.
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Author contributions: Spyros P. Gialamas: data collection, analysis and interpretation, manuscript writing; Eleni Th. Petridou: study design, implementation and quality control supervision, data interpretation, manuscript writing; Sofia Tseleni-Balafouta: adiponectin receptor data determination and interpretation; Themistoklis N. Spyridopoulos: field data collection and interpretation; Ioannis L. Matsoukis: field data collection and interpretation; Agathi Kondi-Pafiti: paraffin block data collection; George Zografos: access to data collection and data interpretation; Christos S. Mantzoros: supervision of hormonal determinations, data interpretation, manuscript writing.