Mini-reviewMetabolic syndrome: A novel high-risk state for colorectal cancer
Introduction
Many disorders can be induced by excessive accumulation of visceral adipose tissue, and the combination of related symptoms, so-called metabolic syndrome (MS), is attracting increasing attention as a major health problem since it can lead to conditions such as cardiovascular disease. Recently, MS has also attracted much interest as a risk factor for several cancers, including colon cancer. The World Cancer Research Fund and American Institute for Cancer Research have evaluated causal relationships between accumulation of visceral adipose tissue and cancer, and concluded ‘confident evidence’ for colorectum and pancreas cancers [1]. In Japan, overweight and obesity, defined as a body mass index (BMI) of 25 or more, are similarly reported to be associated with several cancers, such as colorectum cancer in males, breast cancer in postmenopausal females and liver cancer in those with a history of hepatitis C virus infection [2], [3], [4].
In this review article, relationships between the symptoms of MS and colorectal carcinogenesis are focused on in animal models. Commonly used animals for MS models are rodents because of their size. The models are classified into three groups: diet-induced obesity models (C57BL/6J mice and F344 rats), monogenic models (ob/ob mice, db/db mice, ZDF rats and KK-Ay mice), and polygenic models (TSOD mice and OLETEF rats). A high-fat/-fructose diet, or mice with genetic alterations such as mutation of leptin, leptin receptor and agouti genes are commonly used. Suitable animal models of MS-associated carcinogenesis might be mice with intact leptin and leptin receptors because leptin signaling stimulates cell growth, and may affect carcinogenesis.
Section snippets
Metabolic syndrome
MS is common in Western countries, and is currently increasing almost ubiquitously across the globe. In addition to developed countries, MS is increasing in developing countries in adults and particularly in children [5]. Moreover, obesity and overweight are rapidly increasing in both urban and rural areas in the under developed countries of sub-Saharan Africa and South Asia [6].
Various diagnostic criteria for MS have been proposed by many national/international organizations [7], [8], [9], [10]
Dyslipidemia
Hypertriglyceridemia is associated with an elevated risk (HR = 1.71) of colon cancer in Japanese men [14]. In the case of a precursor lesion of colorectal cancer, most epidemiological studies have consistently showed that serum TG levels are associated with their increase [15], [16], [17], [18]. Thus, it is considered that serum TG, lipoprotein lipase (LPL), a key enzyme that catalyzes the hydrolysis of TG, could play important roles in carcinogenesis.
In animal models of human familial
Diabetes
Insulin resistance is characteristic of metabolic syndrome, associated with high levels of fasting glucose, insulin and insulin-like growth factor (IGF-1) in the blood. It is considered that these conditions are linked to T2DM, and a higher risk of colon cancer [25], [26]. For example, hyperglycemia, hyperinsulinemia and high level of IGF-1 have been demonstrated to increase cell viability and proliferation observed in an in vitro setting [27].
Multiple genetic alterations in tumor-related genes
ROS and inflammation
As mentioned in the previous section, DNA damage induced by ROS is likely to play an important role in carcinogenesis, and obesity increases ROS levels in adipose tissue and blood. In MS patients, abdominal fat tissue attracts macrophages by induction of several chemokines, such as monocyte chemoattractant protein-1 (MCP-1), and forms crown-like structures [13]. Activated macrophages are known to produce ROS and inflammatory cytokines, and thus obesity is now considered to be a pro-inflammatory
Adipocytokine imbalance
Obese mice, such as the KK-Ay strain, are highly susceptible to induction of colon premalignant lesions, aberrant crypt foci (ACF), and development of colorectal carcinomas on exposure to azoxymethane (AOM) [52]. KK-Ay mice were established by cross-mating KK, T2DM model mice, with C57BL/6J-Ay mice [53], [54], which carry the Agouti gene (Ay), and feature severe hyperphagia, hyperinsulinemia and dyslipidemia. C57BL/6J mice are generally used as non-obese controls [55], [56]. The numbers of
Angiotensin-renin system
Activation of the renin–angiotensin system (RAS) has been implicated in the etiology of hypertension, obesity and metabolic syndrome [81]. Angiotensin II (Ang II) elicits its biological activities through two well-defined receptors, type 1 (AT1R) and type 2 (AT2R), to elevate blood pressure, and agents that block AT1R, angiotensin-converting enzyme (ACE) activity and calcium influx block such elevation. It is not clear whether hypertension affects neoplasia, but accumulating evidence suggests
Future aspects
Understanding the molecules involved in obesity-associated cancer may provide clues to cancer preventive strategies in obese individuals. There appears to be a convergence of effects of dyslipidemia, insulin resistance, inflammation and adipocytokines. Targeting related molecules and signaling pathways may therefore be a good preventive and/or therapeutic approach. Some studies suggest that weight loss after gastric bypass surgery is associated with a reduced incidence of cancer [96]. Its
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