Obesity-Related Colorectal Cancer: The Role of Leptin.

Abstract

Obesity is linked to increased risk of colon cancer. Consequently, rising levels of obesity worldwide are likely to have a significant impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases the risk of colon cancer is, thus, a focus for research on strategies to prevent the increasing trend in obesity-related cancers. The epidemiological evidence clearly indicates common factors linking obesity and colon cancer. Both are associated with consumption of high-energy diets, a sedentary lifestyle, increased age and reduced consumption of fruit, vegetables and fiber [1-3]. All these factors influence adipose tissue, now firmly established as the body’s largest endocrine organ [4]. These factors have the potential to influence the production of adipose-derived hormones and cytokines from the adipose organ [5-8]. Leptin and adiponectin are two of the most abundant and most investigated adipose-derived hormones. Friedman and Halaas [9] positionally cloned the ob gene and demonstrated that it was encoded for a hormone that they called leptin (after the Greek ‘leptos’ for thin). The proposed role of leptin was as a growth factor in the colon, stimulating proliferation of the colon epithelium and inhibiting apoptosis. That leptin increased colon tumor growth in obese patients subsequent to the initiation of colon cancer. Leptin is important for colorectal cancer (CRC) growth in obese patients and acts as a growth factor for CRC at stages subsequent to tumor initiation in colorectal carcinogenesis [10]. However, leptin failed to promote the growth of colon cancer xenografts in nude mice and did not increase intestinal tumorigenesis in ApcMin/ + mice [11]. The present study also failed to demonstrate the impact of leptin for increasing tumorigenesis and improving the prognosis. Moreover, an inverse association of nodal stage with high leptin expression was found. Therefore, the authors concluded that a higher leptin expression level was a predictor of a better oncologic outcome and that high leptin expression in colorectal-cancer tissue might be a good prognostic factor. Assessment of leptin signaling in tumor tissue needs further investigation to determine its possible impact on prognosis [12]. The complexity of this issue is confounded by various aspects associated with leptin production and signaling in human coloncancer patients. Leptin receptors are expressed by normal colon epithelial cells in human subjects [13, 14]. High expression of the long-form signaling receptor, ObRb, has been associated with increased age, proximally-located tumors, and high levels of microsatellite instability and lymphocyte infiltration [13]. The impact of plasma leptin is confounded by inconsistent and conflicting data reported from studies on patients with colon cancer [15-20]. A more recent report failed to determine significant differences in serum leptin between patients with colon cancer and controls [15]. The conflicting reports may be due, in part, to cachexia and anorexia, which are common in patients with CRC [21]. Leptin expression in colon tissue may be positively correlated with tumor features that are associated with improved survival of patients with CRC [22]. At present, the significant relationship between leptin expression and clinicopathological details, such as tumor stage and prognosis, suggests a possible role for leptin as a novel growth factor driving the development and the progression of CRC. Large clinical studies are needed to determine the mechanisms underlying the effects of leptin on the development and the progression of CRC.