Obesity-induced metabolic stresses in breast and colon cancer

Authors


Mi-Kyung Sung, Department of Food and Nutrition, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742, Korea. mksung@sm.ac.kr

Abstract

Epidemiological studies have suggested that excess body weight gain may be a major risk factor for colon and breast cancer. A positive energy balance creates metabolic stresses, including the excess production of reactive oxygen species (ROS), hyperinsulinemia, the elevated adipokine secretion, and increased gut permeability. Obesity is a risk factor for breast cancer in postmenopausal women, and overweight women are more likely to have poor outcomes. The higher circulating concentration of insulin-like growth factor 1 (IGF-1) in overweight and obese women is thought to be an important mediator to promote cell proliferation and survival via the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/p38 signaling pathways. In an animal model of colon carcinogenesis, overweight mice fed a high-fat diet exhibited a greater number of colon tumors than lean animals. The increased abdominal fat was associated with higher concentrations of leptin, insulin, and IGF-1, which possibly mediate tumor growth. These data suggest that the metabolic burden created by excess adiposity accelerates uncontrolled cell growth and survival, thereby increasing the risk of developing breast and colon cancer.

Introduction

It has recently been reported that there are an estimated 12.7 million new cancer cases worldwide and that 7.6 million cancer deaths occurred in 2008.1 Lung cancer is the most common cancer and is followed by breast and colorectal cancer. There are indications that global cancer incidence will continue to increase, and cancer prevention strategies including nutritional habits and physical activity will be very important. However, despite a great effort to reduce cancer deaths by implementing dietary modifications, limited progress has been made possibly due to the very complicated nature of the diet and difficulties in behavioral modifications.

Experimental studies have suggested that plant food components exert beneficial effects to suppress cancer development through a variety of different mechanisms. However, from human intervention trials, rather subtle data concerning plant food components and cancer have been obtained.2–4 Recent epidemiological studies have strongly suggested that excess body weight gain may be a major risk factor in many cancers, especially cancers of the colon and breast. A summary report of the World Cancer Research Fund and the American Institute of Cancer Research indicated that the maintenance of a healthy weight (body mass index [BMI] between 21 and 23) throughout the life span is one of the most important ways to protect against cancer.5

Unfortunately, the percentage of adults who are overweight or obese has greatly increased worldwide. The National Center for Health Statistics of the United States indicated that the age-adjusted prevalence of obesity was 33.8% in 2007–2008, and the corresponding prevalence estimates for overweight and obesity combined were 68.0%.6 The National Health and Nutrition Examination Surveys of Korea have reported that the percentage of adults with a BMI ≥ 25 was 31.7% in 2008. The steady increases in obesity and an overweight population are attributed to increases in energy consumption and decreases in physical activity, creating an energy imbalance contributing to the steady increases in cancer incidence. In this review, the current understanding of obesity, metabolic stresses, and cancer development, in particular, breast and colorectal cancer, is summarized.

Metabolic stress and energy imbalance

Energy supply is a vital component of life. Dietary macronutrients including carbohydrates, fat, and protein provide energy as chemical energy and heat. Metabolic stresses are derived from an excess metabolic burden, mostly energy overload. Categories of metabolic stresses related to excess energy intake and obesity include excess production of reactive oxygen species (ROS), hyperinsulinemia, elevated adipokine secretion, and increased gut permeability (Fig. 1).

Figure 1.

Energy overload and metabolic stresses. Metabolic stresses are derived from nutrient overload, which supplies excess energy. Metabolic tissues including the liver oxidize macronutrients through the TCA cycle, and incomplete oxidation produces ROS, which increase oxidative stresses. The excess energy is converted to fat and stored in adipocytes. The accumulation of fat increases circulating concentrations of insulin, IGF-1, and adipokines, which lead to insulin resistance and abnormal cell growth. Increases in fat mass actively attract immune cells, thereby creating inflammatory conditions. Nutrient overload also increases intestinal cell membrane permeability, possibly through changes in gut flora composition followed by immune cell recruitment. Abbreviations: TCA (tricarboxylic acid), ROS (reactive oxygen species), ER (endoplasmic reticulum), IGF-1(insulin-like growth factor-1), GI tract (gastrointestinal tract).

The tricarboxylic acid (TCA) cycle oxidizes the metabolites of macronutrients to form the reduced nicotinamide adenine dinucleotide (NADH + H+) and the reduced flavin adenine dinucleotide (FADH2). High-energy electrons from NADH and FADH2 enter the electron transport chain and produce ATP. This process is called oxidative phosphorylation, and macronutrients supplied in excess of the body's energy needs are converted to fat and stored in the adipose tissue. During this oxidation process, two electrons are transferred and combined with 1/2 O2 to form H2O. In the meantime, incomplete oxidation also occurs, producing superoxide (O2), which is a source of ROS. The most common ROS include superoxide anion, hydroxyl radicals, and hydrogen peroxide. ROS are extremely reactive to cellular components and cause DNA, protein, and lipid modifications. In normal circumstances, endogenous antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, catalase, as well as exogenous antioxidants, such as vitamin C, vitamin E, and polyphenols, effectively scavenge ROS. However, the elevated level of ROS and/or defective defense mechanisms increase oxidative stress and cellular damage, which are closely related to aging and the development of chronic diseases, including cancer. Recent studies have suggested that ROS regulate cell survival and cell death via the activation of major signaling pathways.7,8 ROS have been shown to activate nuclear factor-kappa B (NF-κB), which is a central coordinator of immunity, inflammation, cell differentiation, and survival.9

Energy metabolism is subject to tight hormonal regulation. Insulin and glucagon are the most representative hormones exerting opposite metabolic effects. The postprandial increase in insulin accelerates the tissue uptake of glucose and drives the metabolism toward the synthesis of glycogen and fat. Nutrient overload, followed by an increase in adipose tissue mass, creates hyperinsulinemia, which stimulates receptor-mediated signaling of insulin, including the activation of MAPK cascades and related modulation of gene expression. The activation of inflammatory NF-κB pathway is shown to be a key mediating signal to produce inflammatory cytokines followed by insulin resistance.10 Additionally, obesity is related to excess production of free fatty acids and inflammatory cytokines, which, in turn, induce insulin resistance.

Metabolic stresses induced by excess energy intake are also caused by increases in body fat mass. It has been shown that dynamic crosstalk exists between the adipocytes and immune cells, which suggests that fat tissue is an important mediator of inflammatory responses in many chronic disease conditions. Adipose tissue comprises adipocytes, preadipocytes, macrophages, lymphocytes, and endothelial cells, which enable the tissue to be metabolically and immunologically active. Adipocytes produce adipocytokines (leptin, adiponectin, resistin), cytokines (tumor necrosis factor [TNF]-α, interleukine [IL]-6, IL-1) and chemokines (CC-chemokine ligand 2 [CCL2]).11 CCL2 contributes to macrophage infiltration into adipose tissue.12 Adipose tissue also expresses toll-like receptor (TLR) subsets, which are linked to the activation of NF-κB followed by the production of proinflammatory cytokines and chemokines.13

More recently, the interrelationship among gut flora, gut permeability, and obesity has received attention. Alteration in the intestinal barrier has been proposed to be associated with intestinal and liver disorders, autoimmune diseases, and diabetes. Evidence suggests that a leaky gut might be a causative factor predisposing one to inflammatory disease development,14 although no clear explanation has been provided. The increased gut permeability allows the passage of luminal antigens, which induce autoimmune reactions in a target tissue, such as insulin-producing β cells.15 Additionally, the increased intestinal permeability exerts local inflammatory type responses contributing to systemic inflammation followed by metabolic alterations such as insulin resistance. Other studies have also indicated that diet-induced obesity or dietary fat feeding increases metabolic inflammation by increasing intestinal permeability through changes in gut flora populations.16,17

Metabolic stress in breast cancer

The incidence of breast cancer in women is increasing in most countries, particularly in countries where the incidence used to be relatively low.18,19 Breast cancer development is closely related to hormonal and genetic factors. Lactation is suggested as a strong protective factor against breast cancer. Lactation is associated with lower exposure to endogenous sex hormones and increased elimination of breast epithelial cells by apoptosis at the end of lactating period.

A great deal of effort has been made for many years to explain the relationship between diet and breast cancer. Dietary fat is a source of endogenous estrogen and has been suggested as a possible risk factor. However, prospective cohort studies have shown inconsistent effects, suggesting that dietary fat per se may not increase the risk.20 In contrast to the inconclusive relationship between dietary components and breast cancer, convincing data have shown that body fatness increases the risk of breast cancer in postmenopausal women.5 A pooled analysis of seven prospective cohort studies comprised 337,819 women, and 4,385 incident invasive breast cancer cases indicated that the pooled relative risk of breast cancer was 1.26 (95% CI: 1.09–1.46) when a BMI > 28 kg/m2 was used as the highest category in the categorical analyses in postmenopausal women.21 However, the inverse association was found in premenopausal women. Being overweight or obese is also associated with poorer prognosis and increased recurrence. Among 34 studies looking at the relationship between survival/recurrence and obesity/weight gain in early-stage breast cancer patients, 26 studies found significantly positive associations.22

Estrogen production in premenopausal women occurs mainly in the ovaries, while the ovarian production of estrogen is replaced by adipose tissue in postmenopausal women.23 Epidemiological data have suggested that serum estrogen concentration is a risk factor for breast cancer in postmenopausal women.24 Therefore, the cancer-promoting role of body fat has been attributed to the higher local production of estrogen, thereby providing an explanation for the connection between postmenopausal breast cancer risk and body fatness. However, an inverse association between body fatness and breast cancer risk in premenopausal women may not be fully justified by the previous explanations. Experimental studies have suggested that estrogen deprivation decreases insulin sensitivity and increases atopic fat accumulation in high fat–fed mice, suggesting a protective role of estrogen in metabolic alteration.25–27 Therefore, the increased breast cancer risk in obese postmenopausal women may be partly explained by hyperinsulinemia resulting from estrogen depletion and excess accumulation of fat tissue (Fig. 2).

Figure 2.

Two faces of estrogen. Estrogen promotes breast tumor growth by receptor-mediated cellular signaling pathways such as MAPK and PI3K signals. Estrogen metabolites induce DNA mutation, thereby initiating carcinogenesis. In postmenopausal women, estrogen deprivation blocks AMPK activation inducing atopic fat accumulation followed by IR-mediated activation of Akt and mTOR, possibly accelerating abnormal cell growth. On the other hand, the postmenopausal body fat accumulation induces the activation of adipocyte stromal cell aromatase through PKC-mediated signaling and produces estradiol, promoting breast tumor formation. Abbreviations: E2 (estradiol), ER (estrogen receptor), ERE (estrogen-responsive element), MAPK (mitogen-activated protein kinase), PI3K (phophoinositide 3-kinase), p-AMPK (phosphorylated AMP-activated protein kinase), mTOR (mammalian target of rapamycin), FFA (free fatty acid), IR (insulin receptor), IRS-1 (insulin receptor substrate-1), PKC (protein kinase C), COX-2 (cyclooxygenase-2), PGE2 (prostaglandin E2), cAMP (cyclic adenine monophosphate), PKA (protein kinase A).

IGF-1, an insulin-related protein, is known to function as a growth factor for mammary epithelium.28 Epidemiological studies have shown that women with elevated blood concentrations of IGF-1 exhibit an increased risk of breast cancer.29,30 The elevated circulating level of insulin indirectly affects tumorigenesis by regulating IGF-1 synthesis, a mechanism that has been implicated in the regulation of cell cycles and apoptosis.31 The IGF-1 receptor (IGF-1R) and insulin receptor (IR) have been reported to be overexpressed in breast cancer cells and tissue specimens.32 Insulin receptor substrate (IRS)-1, a major substrate for IR and IGF-1R, activates survival signaling via the PI3K/Akt and MAPK/p38 pathways promoting cancer cell proliferation and survival.33,34

Rodent studies have also indicated an association between serum IGF-1 concentration and mammary cancer risk. LID mice carrying a hepatic IGF-1 gene deletion showed a dramatic reduction in serum circulating IGF-1 levels and the delayed onset of chemically and genetically induced mammary tumors.35 Rats fed a calorie-restricted diet exhibited decreased serum insulin and IGF-1 concentrations, which may be related to the suppression of mammary tumor growth in these animals.36 Therefore, increases in circulating IGF-1, which results from excess dietary energy intake, may be one of the major key links between excess energy supply and breast cancer risk.

The higher circulating concentrations of pro-inflammatory cytokines are suggested to have a close relationship with breast cancer risk.37 We have also found that proinflammatory IL-1β and IL-6 concentrations are significantly higher in breast cancer patients compared to those of the age-matched control subjects.38 Insulin resistance has been associated with the increased production of TNF-α and IL-6.39–41 These cytokines are shown to promote tumor cell growth by regulating the expression of antiapoptotic and angiogenic proteins.42,43 In highly metastatic breast cancer cells (MDA-MB231), AP-1 and NF-κB are shown to have a prominent role in IL-6 gene transcription.44 These cytokines are also inducers of aromatase and possibly increase the circulating estrogen concentration.45

Metabolic stress in colon cancer

Excess body fat and abdominal fatness have been reported as convincing risk factors of colorectal cancer (CRC).5 The risk of CRC is reported to increase by 7% as BMI increases by 2.46 The results of one meta-analysis also revealed a 5% increased risk of CRC per inch of waist circumference, an indication of abdominal fatness.5 Abdominal fatness is associated with the circulating concentrations of hormones, growth factors, and inflammatory cytokines, which accelerates uncontrolled cell growth, possibly leading to the development of cancer.

Hyperinsulinemia in relation to colon cancer development has been reported. Epidemiological studies suggested hyperinsulinemia assessed by measuring plasma C-peptide is related to an increased risk of colon cancer.47 Type 2 diabetes patients are shown to have three times higher risk of developing colon cancer.48In vitro studies have demonstrated that insulin promotes colon cancer cell proliferation.49,50 Hyperinsulinemia decreases the concentration of the IGF-1 binding protein (IGFBP-1), which increases circulating free IGF-1.51 IGF-1, as a key mitogen to accelerate cell cycle progression, increases the risk of cellular transformation due to rapid cell turnover.52 The binding of insulin to its receptor phosphorylates insulin receptor substrates, IRS-1 or IRS1/4, thereby stimulating the downstream signaling.53 The activation of IRS-1 and IRS1/4 is shown to stimulate the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) signaling pathway and the PI3K/Akt signaling pathway, respectively, regulating cell proliferation, survival, growth, and motility processes that are critical for colon tumorigenesis.51,54,55 Leptin, an adipocyte-derived peptide hormone, belongs to the cytokine family and controls appetite to modulate energy balance. It is produced proportional to body fat, and obese subjects showed chronically elevated levels of circulating leptin.56 The synthesis of leptin in adipose tissue is influenced by insulin,57 and this may also contribute to the high leptin concentration in obesity. Despite a lack of direct evidence that an increased leptin concentration is a risk factor for colon cancer, studies have proposed that higher leptin concentrations may be a possible link between obesity and the development of colorectal cancer.58,59In vitro studies have provided evidence that leptin modulates the proliferation of LS174T and HM7 colon adenocarcinoma cells.60

As the colon is not generally considered as a major target tissue for the insulin action, few experimental studies have been conducted to determine whether obesity-induced hyperinsulinemia contributes to colon tumor development. We have recently conducted a study to investigate molecular mechanisms of diet-induced obesity in colon carcinogenesis in a mouse model of colitis-associated colon cancer.61 In this study, animals were fed either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. The colon tumor was induced by a single intraperitoneal injection of azoxymenthane (10 mg/kg body weight) followed by two one-week cycles of disodium sulfate supply. Results from this study clearly demonstrated that the HFD feeding increased the number of colonic tumors, two times higher than that in animals fed the ND. The HFD-induced epididymal fat deposition was associated with increases in circulating insulin, IGF-1, and leptin, as well as the mRNA levels of epididymal fat pad leptin and colonic leptin receptor (Ob-R). Additionally, the animals fed the HFD showed higher levels of the Ob-R, IR, phosphorylated Akt, phosphorylated ERK, Bcl-xL, and cyclin D1 proteins in the colon. From these results, it can be speculated that obesity facilitates colon tumor formation, possibly through increases in blood insulin, IGF-1, and leptin, which induce activation of their corresponding receptors in the colon and subsequently induce PI3K/Akt and ERK1/2 pathways.

Obesity is associated with chronic low-grade systemic inflammation. As in the case of obesity-related breast cancer risk, adipocyte-derived factors have been suggested to mediate inflammatory responses in colon cancer. Adipocyte-derived leptin increases TNF-α production,62 and insulin was shown to increase IL-6 expression of adipocytes.63 Because TNF-α and IL-6 are proinflammatory cytokines promoting cell proliferation and survival, these data clearly suggest that obesity increases the risk of colon cancer by inducing chronic inflammation and activating downstream cellular signaling.

Conclusion

It is only in recent years that body fatness has been suggested as a most convincing risk factor for developing cancer of the breast and colon. At the same time, adipocytes, which had been considered an inert storage organ, are receiving attention as a center of metabolic intergration. So far we only have pieces of information that have not been pulled together to create a complete picture. Nevertheless, it is clear from the existing evidence that adipocytes induce metabolic stress in coordination with immune cells, which may explain accelerated cell growth and survival in cancerous tissues. Further studies to elucidate the signaling network between adipokines and mediators of immune responses are required in order to establish intervention targets.

Acknowledgments

This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (2008-0060833), and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0001886).

Conflicts of interest

The authors declare no conflict of interest.

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