Sage Journals: Discover world-class research

Abstract

There is increasing recognition of the impact of being overweight and obese on the development of cancers at diverse sites including the gastrointestinal tract. Large epidemiological studies indicate that up to 14% of tumours may be related to obesity. Pathophysiological mechanisms underpinning this association are not well understood and so are discussed in this review.

Keywords

visceral adiposity inflammation adipose tissue,carcinogenesis signalling pathways

The obesity problem

The rapidly increasing prevalence of obesity is a major public health concern. The overweight or obese body habitus has now become the norm. In the United States, 71% of men and 62% of women are overweight or obese [Ogden et al. 2006]. Rates are increasing in a similar fashion in Western Europe with 65% of men and 56% of women being overweight or obese in the United Kingdom [Zaninotto et al. 2006]. Obesity prevalence shows no signs of decreasing.

Adipose tissue is principally deposited in two compartments: subcutaneously and centrally. It is thought that centrally deposited, or visceral, fat is more metabolically active than peripheral subcutaneous fat [Galic et al. 2010; Kershaw and Flier, 2004; Vohl et al. 2004]. Visceral adipose tissue is largely composed of omental adipose tissue but also includes other intra-abdominal fat sources such as mesenteric fat. Visceral adipose tissue secretes a number of adipokines and cytokines leading to a pro-inflammatory, procoagulant and insulin-resistant state collectively known as metabolic syndrome [Despres and Lemieux, 2006] (Figure 1).

Figure 1.

Excess visceral adipose tissue results in systemic inflammation. The expanded adipose tissue mass in patients who are viscerally obese is infiltrated with macrophages and activated T cells. These cells, as well as the increased number of adipose cells, produce factors which result in a state of systemic inflammation which is thought to increase tumourigenesis.

The importance of adipose tissue location in terms of dysmetabolism risk is evident as central obesity is more strongly associated with increased risk of insulin resistance, metabolic syndrome and cardiovascular diseases than body mass index (BMI) alone [Nedungadi and Clegg, 2009]. For any given amount of total body fat, the subgroup of individuals with excess visceral fat (versus subcutaneous fat) is at higher risk of developing insulin resistance [Kissebah et al. 1982] and the features of metabolic syndrome [Despres et al. 1990]. Visceral fat remains more strongly associated with an adverse metabolic risk profile even after accounting for the contribution of other standard anthropometric indices [Snijder et al. 2006]. These systemic effects exerted by visceral adiposity are putatively involved in cancer biology [van Kruijsdijk et al. 2009]. In patient studies it can be difficult to ascertain the differential effects of visceral versus subcutaneous adipose tissue as most humans possess deposits of both albeit in differing ratios. A recent mouse study involving ^{Apc 1638N/+} female mice which are genetically predisposed to the early development of colonic adenomas and, hence, cancers sought to determine whether visceral fat independent of other confounders is causally linked to colonic tumourigenesis [Huffman et al. 2013]. In order to do so, the visceral fat was surgically removed from these mice and the outcomes of three groups, ad libitum fed, visceral fat removal and ad libitum fed or visceral fat removed and caloric restriction, were compared. Macroadenoma rate was attenuated by removal of visceral fat but not affected by calorie restriction indicating an independent effect of visceral fat on tumourigenesis.

The simplest direct measure of central obesity is waist circumference (WC). Over the past decade in the United States mean BMI and WC measurements have increased, particularly amongst men with the mean BMI in 2008 of 28.5kg/m² and mean WC of 100.8cm [Ford et al. 2011]. The prevalence of abdominal obesity (WC >102 cm in men and >88 cm in women) was 43.7% in men and 61.8% in women [Ford et al. 2011].

Obesity rates are increasing amongst children [Troiano and Flegal, 1999] and overweight children tend to become overweight adults [Serdula et al. 1993]. Obesity rates are increasing exponentially: rates have doubled in Australia over the last 20 years [Dunstan et al. 2002] and in the United States over the last 30 years (see the 1971–1974 and 2003–2006 National Health and Nutrition Examination Surveys at http://www.cdc.gov/nchs/fastats/overwt.htm). Over the same time period, European childhood obesity rates have tripled [WHO, 2000].

Obesity and cancer: the epidemiological association

Epidemiological studies have demonstrated a robust link between obesity and cancer development at numerous sites, in particular the oesophagus, pancreas, colorectum, breast (postmenopausal), endometrium and kidney [Calle et al. 2003; Renehan et al. 2008b]. The World Cancer Research Fund estimates up to 28% of gallbladder cancers, 35% of pancreatic, and 35% of oesophageal cancers are attributable to obesity [World Cancer Research Fund, 2007]. This association carries relative risk (RR) estimates of 1.1–1.6 per 5 kg/m² incremental increase in BMI [Calle and Kaaks, 2004]. Obesity also increases cancer-related mortality with studies reporting that obesity could account for 14% of all deaths from cancer in men and 20% in women [Calle et al. 2003]. Furthermore, emerging clinical research suggests weight loss following bariatric surgery leads to a reduction in cancer incidence [Adams et al. 2009; Christou et al. 2008; Sjostrom et al. 2009]. Thus, the potential mechanisms by which obesity increases both the incidence of certain malignancies, and cancer deaths, have become the focus of considerable research.

There appears to a sex differential with respect to risk of cancer development with men having a higher risk of developing cancer at increased BMI than women [Moore et al. 2004; Renehan et al. 2008b]. This may be due to the differing hormonal milieu in females or it may reflect the fact that BMI poorly reflects central adiposity in females. Since females generally only deposit central adipose tissue once total fat volumes are raised, overweight BMIs do not correspond with visceral fat volume in females as they do in males, which may account for the differences in cancer risk seen when BMI is used to determine obesity status.

In studies which use measures of visceral adiposity such as WC or visceral fat area (VFA), visceral adiposity is associated with increased risk of cancer development [Moore et al. 2004; Steffen et al. 2009; Wang et al. 2008], is a stronger predictor of cancer risk than BMI [Moore et al. 2004] and the cancer risk is similar in men and women [Moore et al. 2004; Wang et al. 2008]. Further, larger studies using measures of visceral adiposity across cancer sites are awaited in order to clarify whether there is a clear differential effect of visceral versus subcutaneous obesity.

Obesity has been strongly implicated in the pathogenesis of oesophageal adenocarcinoma. [Brown et al. 1995; Calle et al. 2003; Chow et al. 1998; Engel et al. 2003; Lagergren et al. 1999b; Renehan et al. 2008b; Ryan et al. 2006; Vaughan et al. 1995]. Centrally located fat, independent of overall BMI, is associated with increased risk of developing gastro-oesophageal reflux, Barrett’s oesophagus and oesophageal adenocarcinoma (OAC) [Corley et al. 2007a; Lagergren et al. 1999a]. Intuitively, the raised intra-abdominal pressure due to visceral adiposity places mechanical pressure on the stomach to increase reflux. However, after adjustment for gastro-oesophageal reflux, rates of OAC remain increased amongst those with obesity. Certainly, Barrett’s oesophagus seems to be more closely correlated with increased WC [Akiyama et al. 2009; Cook et al. 2008; Corley et al. 2007b; Edelstein et al. 2007] than raised BMI [Cook et al. 2008]. Several studies have reported a high prevalence of obesity amongst patients with the only recognized precursor of OAC, Barrett’s oesophagus [Corley et al. 2007a; Healy et al. 2010].

In pancreatic cancer, the risk of malignancy increases as BMI increases >30 kg/m². Whilst in earlier studies there was a degree of inconsistency in correlations between obesity and pancreatic cancer, recent research has shown a more consistent pattern of association, with meta-analyses reporting a RR of 1.07-1.19 [de Gonzalez et al.; Larsson et al. 2007; Renehan et al. 2008b]. In addition, research by Li and colleagues reported that patients who are obese in early adulthood have a greater risk of developing pancreatic cancer and do so at an earlier age than their nonobese counterparts [Li et al. 2009].

A number of meta-analyses have reported a modest but consistent relationship between the incidence of colon cancer and obesity, with a relative risk of 1.24–1.59 in obese men and 1.09–1.22 in obese women [Bergström et al. 2001; Dai et al. 2007; Guh et al. 2009; Harriss et al. 2009; Larsson and Wolk, 2007a; Moghaddam et al. 2007; Renehan et al. 2008b]. The risk is greater for cancer of the colon than of the rectum. Colonic adenomas, the colorectal cancer precursor lesions, have also been associated with increased BMI [Kono et al. 1999; Ya-Yu et al. 2005] and abdominal obesity [Giovannucci et al. 1996; Kim et al. 2009]. The majority of studies have reported a stronger association between obesity and colorectal cancer in men than in women, which has been hypothesized to be due to differential adipose tissue distribution, with increased levels of visceral adiposity observed in man compared with women [Calle, 2007]. However, there is evidence that when WC, rather than BMI, is used to determine obesity status the apparent sex difference is greatly reduced [Pischon et al. 2006].

Epidemiological evidence concerning the association between gastric adenocarcinoma and obesity are limited in number but the most recent meta-analysis there was no association. Gallbladder and biliary carcinomas may be associated with obesity although whether this factor directly mediates an effect or whether the effect is mediated by the increase prevalence of gallstones in obese patients is not clear [Larsson and Wolk, 2007b]. Data concerning hepatocellular carcinoma are subject to many confounding factors which may be difficult to control for including alcohol, infectious agents and the uncertain significance of nonalcoholic hepatosteatosis. Overall there appears to an association with obesity with a population attributable rate of approximately 30% [Larsson and Wolk, 2007c].

Mechanisms underpinning the association between obesity

To date the mechanisms which mediate the obesity-driven effect on cancer development and progression in humans have been poorly understood. Difficulties arise in controlling for confounding factors such as systemic energy balance, physical activity and nutrition and most of the relevant data on mechanisms rely on animal or in vitro studies. Hypothesis relevant to the question and explored in this review, are whether obesity affects tumours via alterations in the systemic cytokine, hormonal and growth factor milieu and whether this is aligned to the presence of systemic inflammation in obesity and, second, whether obesity results in the upregulation of oncogenic pathways represented by increased activity of signalling pathways such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) pathways.

Obesity is a state of chronic systemic inflammation

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass [Galic et al. 2010]. Increased adipose tissue mass, especially visceral adipose tissue, is associated with insulin resistance, hyperglycaemia and dyslipidemia. Mobilization of free fatty acids (FFAs) is more rapid from visceral than from subcutaneous fat cells because of the higher lipolytic activity in visceral adipocytes, in both nonobese and obese individuals, particularly in the latter, which probably contributes significantly to the FFA levels in the systemic circulation of obese individuals [Snijder et al. 2006]. The higher lipolytic activity in visceral fat in comparison with subcutaneous fat can be attributed to regional variation in the action of the major lipolysis-regulating hormones, catecholamines and insulin; the lipolytic effect of catecholamines being more pronounced and the antilipolytic effect of insulin being weaker in visceral than in subcutaneous adipose tissue [Wajchenberg, 2000]. In addition, specific proteins and hormones produced by omental and mesenteric adipose tissue, such as inflammatory molecules, angiotensinogen and cortisol can also contribute the systemic inflammatory condition associated with obesity. Excess adipose tissue results in elevated levels of pro-inflammatory adipokines, resulting in an imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanism leading to persistent low-grade inflammation [Das, 2001; Esposito and Giugliano, 2004; Wajchenberg, 2000] (Figure 1).

Insulin resistance and type 2 diabetes mellitus (T2DM) have been recently recognized as intimately associated with the presence of systemic inflammation. Obesity is associated with an increased risk of developing insulin resistance and T2DM. Nutritionally induced insulin resistance develops as a metabolic adaptation to increased circulating levels of FFAs, which are constantly released from adipose tissue, especially from visceral fat stores [Calle and Kaaks, 2004]. Increased FFA levels force liver muscle and other tissues to shift towards increased storage and oxidation of fats for their energy production [Bergman and Ader, 2000]. The compensatory effect is a reduced capacity of these tissues to absorb, store and metabolise glucose. In tandem, markers and mediators of systemic inflammation including acute phase reactants such as fibrinogen, C-reactive protein, interleukin (IL)-6, plasminogen activator inhibitor-1 (PAI-1) and white cell count are raised in patients with newly diagnosed T2DM [Shoelson et al. 2006].

Increased numbers of adipocytes releasing FFAs alone are not sufficient for the development of insulin resistance. In addition to increased FFA levels, high concentrations of cytokines produced by adipose tissue, such as tumour necrosis factor (TNF)-α, IL -6 and IL-1β, and low concentrations of adiponectin are required for deleterious effects on glucose homeostasis [Greenberg and McDaniel, 2002]. The cellular and molecular mechanisms leading to insulin resistance includes a reduction in cellular insulin-receptor levels and reduced responsiveness of some intracellular transduction pathways mediating the effects of insulin binding to its receptor [Moller and Flier, 1991]. Insulin resistance leads to increased insulin production and insulin can act as a mitogen and has been associated with several cancers [Colangelo et al. 2002; Schoen et al. 1999; Trevisan et al. 2001]. The tumourigenic effects of insulin could be directly mediated by insulin receptors in the preneoplastic target cells, or might be due to related changes in endogenous hormone metabolism, secondary to hyperinsulinaemia [Calle and Kaaks, 2004].

The mitogenic and potentially procarcinogenic effects of insulin have been hypothesized but unproven for decades [Donohoe et al. 2011]. The most exciting development with respect to the this field of study in recent years is the observation that biguanide medications, such as metformin, have been associated with a reduction in the insulin levels of patients with T2DM and appear to be associated with a decreased risk of cancer incidence. It is not understood whether this is mediated via the reduction in insulin and, hence, its direct effects or also via the alteration in signalling and metabolism induced by these medications [Pollak, 2012].

The obese state represents an altered immunological milieu

Visceral adipose tissue, in addition to being more metabolically active, is also an immunologically enriched environment. Cytokines secreted by adipose tissue include the following pro-inflammatory cytokines: TNF- α, IL-6, IL-8, IL-10, IL-1 receptor agonist (IL-1Ra), macrophage inflammatory protein 1(MIP-1) and monocyte chemoattractant protein 1 (MCP-1). These cytokines are directly influenced by the degree of immune infiltrate in adipose tissue, which in turn is influenced strongly by the degree of adiposity of the expanded fat mass. In obese patients, the increased size and number of adipocytes in adipose tissue results in areas of hypoxia within the tissue. This hypoxia induces the secretion of inflammatory factors in order to promote angiogenesis [Feldser et al. 1999; Fukuda et al. 2002; Trayhurn and Wood, 2004]. Inflammatory cytokines attract infiltrating immune cells which in turn produce more inflammatory cytokines. In fact, the overall level of adipokine production from adipose tissue is strongly influenced by the degree of immune cell infiltration present in adipose tissue [Kershaw and Flier, 2004; Schaffler et al. 2006; Weisberg et al. 2003; Xu et al. 2003]. Adipose tissue in obese people is infiltrated with macrophages and the number of macrophages correlates with the degree of adiposity [Neels and Olefsky, 2006]

Peripheral monocytes are recruited by MCP-1 and TNF-α, and can differentiate into activated macrophages [Curat et al. 2004]. The products of activated macrophages can have an impact on adipocyte function and are postulated to be involved in altering adipose tissue glucose handling and thus contribute to insulin resistance [Sartipy and Loskutoff, 2003; Wellen and Hotamisligil, 2003]. Research has shown that coculture of adipocytes with macrophage-conditioned media causes increased adipokine and inflammatory cytokine production by adipocytes [Bassols et al. 2009], further supporting this hypothesis. Increased release of inflammatory cytokines by obese adipose tissue had a profound influence on immune cells both locally and systemically.

T-cells may also be key regulators of adipose tissue inflammation. Nishimura and colleagues demonstrated a significant increase in CD8⁺ T-cell infiltration into expanding visceral adipose tissue, which preceded macrophage infiltration. These T cells were found to be responsible for both the establishment and maintenance of adipose tissue inflammation in obesity [Nishimura et al. 2009]. Further work by Lysaght and colleagues investigated human omentum harvested from OAC patients and demonstrated that it is a particularly rich source of CD8⁺ T cells. A high percentage of CD4⁺ and CD8⁺ omental T cells were activated with an inflammatory T-helper 1 phenotype (CD69⁺ CD45RO⁺ IFN-γ⁺). Of particular interest was the finding that there were significantly more interferon-γ+ T cells present in the omentum of cancer patients compared with noncancer controls [Lysaght et al. 2011]. The role of T cells in adipose tissue inflammation and cancer has not received much attention so far but offers potential immunotherapeutic targets for obesity-associated morbidities

Obesity is also associated with an alteration in the function of circulating immune cells. Studies have found decreased T- and B-cell function, increased monocyte and granulocyte phagocytosis and oxidative burst, and raised total leukocyte counts [Mendall et al. 1997; Nieman et al. 1999]. Circulating mononuclear cells from obese subjects have been shown to exhibit increased nuclear factor b (NFB) nuclear binding with decreased levels of NFκB inhibitor and increased mRNA expression of IL-6, TNF-α and migration inhibition factor. Markers of macrophage activation correlate with plasma levels of FFAs [Ghanim et al. 2004].

Adipokine levels in obese individuals

Systemic chronic inflammation and an altered immune profile may exert effects on the tumour microenvironment. Obese rat models have increased inflammatory transcription factor expression (TNF-α and NFκB) in their tumours [Jain and Bird, 2010]. Adipokines produced (including IL-6, leptin and vascular endothelial growth factor [VEGF]) from obese fat reservoirs differ from those produced from the fat of patients with normal body weight [Lysaght et al. 2011]. There is interplay between different adipokines with possible positive feedback loops increasing pro-inflammatory adipokines. For example, insulin can modulate adipokine production and including two of the most abundant adipokines: leptin and adiponectin. Insulin is a positive regulator of leptin and increases its gene expression to suppress appetite [Yamauchi et al. 2001]. Circulating levels of leptin positively correlate and adiponectin levels negatively correlate with all measures of obesity (BMI, WC and VFA) [Cummings and Foster, 2003; Howard et al. 2010; Kadowaki and Yamauchi, 2005]. Adiponectin acts as an insulin sensitizing agent [Yamauchi et al. 2001]. In addition to modulation of insulin sensitivity, these adipokines can directly affect tumour cells [Schaffler et al. 2005]. Adiponectin is antitumour: it increases apoptosis [Dieudonne et al. 2006], inhibits proliferation, inflammation and angiogenesis [Brakenhielm et al. 2004] and can prevent the interaction of growth factors with their receptors [Wang et al. 2007]. There is a consistent inverse relationship with cancer incidence and circulating adiponectin [Roberts et al. 2010]. The protumour effects of leptin are the direct opposite of those of adiponectin [Roberts et al. 2010], although the epidemiological association between circulating levels and cancer risk is less consistent [Renehan et al. 2008a].

Another of the differentially expressed adipokines in obesity is insulin-like growth factor (IGF). Serum levels of IGF-1 (in both free unbound and total bound forms) are increased in OAC patients who are viscerally obese versus those who are of normal weight [Donohoe et al. 2012]. IGF-1, similar to other adipokines, can have protumourigenic properties either by binding to and influencing tumour cells directly or by stimulating cells in the tumour’s micro-environment which in turn may have an influence on the survival of tumour cells.

Species of the IGF-1 axis family are expressed in immune cell populations [Oberlin et al. 2009] and tumour-associated macrophages are a source of IGF-1 [Kodelja et al. 1997; Kopfstein and Christofori, 2006; Sunderkotter et al. 1994]. There is an increase in CD68+ cells, a cell surface macrophage marker, in the stromal tissue surrounding the invasive edge of oesophageal tumours [Doyle et al. 2012]. Furthermore, there was increased expression of the insulin-like growth factor receptor in OAC tumour’s invasive edge, which may indicate that there is a paracrine mechanism involving interplay between tumour-associated macrophage-derived IGF-1 and tumour cells which express insulin-like growth factor (IGF1R). Circulating levels of free and total IGF-1 are increased in patients with OAC who are viscerally obese versus their normal-weight counterparts [Donohoe et al. 2012] and IGF1R expression in OAC tumours is a poor prognostic marker [Donohoe et al. 2012]. Whether stimulated by macrophage-produced IGF-1 or systemic circulating IGF-1 species, activation of IGF1T has a proliferative, anti-apoptotic role in cancer cell growth and development.

Signalling pathways and alterations in obesity

Cancers which develop within an obese environment may become selectively altered to signal via specific pathways. For examples, in patients with non-small cell lung cancer, only a subset (approximately 10–20%) respond to the epidermal growth factor receptor (EGFR)-targeted therapy gefitinib, and these patients often have an activating mutation of EGFR [Lynch et al. 2004]. Patients with activating mutations are more likely to have adenocarcinomas, and to be female, nonsmokers and Japanese [Taron et al. 2005]. Similarly, obesity-related cancers may have a specific set of targets (malfunctioning molecules or pathways) which may be exploitable in clinical practice. Certainly a number of the putatively dysregulated adipokines and growth factors in obesity do signal via the same intracellular signalling pathways (Figure 2).

Figure 2.

The obese state of systemic inflammation upregulates intracellular pathways which promote functional aspects of cancer cell. Cancers which develop within an obese environment may become selectively altered to signal via specific pathways. Many of the factors upregulated systemically in the obese state including leptin, interleukin(IL)-6, insulin, tumour necrosis factor and insulin-like growth factor (IGF)-1 all signal via similar candidate pathways include the phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) pathways. Activation of these pathways leads to multiple downstream effects including cell proliferation and cell survival. Illustration courtesy of Alessandro Baliani © 2013.

Candidate pathways include the PI3K, MAPK and STAT3 pathways. Activation of these pathways leads to multiple downstream effects which underpin cancer progression and metastasis [Aggarwal et al. 2009; Huang et al. 2010; Yu et al. 2009]. Importantly, inhibitors of these pathways are under development at present in order to provide new therapeutic avenues [Jing and Tweardy, 2005; Liu et al. 2009; Sebolt-Leopold and Herrera, 2004].

One of the hypothesised pathways strongly implicated in mediating the effect of the obese environment is the PI3K pathway. Activation of PI3K pathway signalling leads to a number of functionally relevant prosurvival effects including growth, proliferation, differentiation, motility, survival and intracellular trafficking [Engelman, 2009]. Many of the factors upregulated in the obesity signal via the PI3K pathway. These include leptin, IL-6, insulin, TNF and IGF-1. Is there any evidence that cancers which develop within the obese milieu are ‘addicted to’ or preferentially signal via these pathways?

Whole-genome analysis of breast cancer tumours divided according to BMI demonstrate that an obesity-associated gene signature pattern is associated with a shorter time to metastasis and is associated with IGF signalling signature in multiple publically available breast cancer genome arrays [Creighton et al. 2012]. There is a high degree of overlap between the genes in this IGF signature with those of constitutive PI3K activity signatures. No such studies to date have been performed in gastrointestinal cancers.

Most data to support this hypothesis are derived from mouse models. PI3K activity (measured by pAkt and mTOR protein levels) is increased in diet-induced obesity in mice and is associated with an increased level of circulating IGF-1 compared with controls [Moore et al. 2008]. Mice fed a high-energy diet have twice the volume of tumours 17 days after colon cancer cell injection versus controls. PI3K pathway activity was demonstrated by increased phosphorylated Akt protein levels. The tumour growth effect was abrogated by metformin treatment, which led to decreased pAkt levels [Algire et al. 2010]. In a mouse model of obesity-related skin cancer, obese mice had higher PI3K activity after UV exposure than lean mice [Sharma and Katiyar, 2010]. Activity of MAPK phosphorylation and NF-kB signalling were also higher following UVB irradiation in leptin-deficient obese mice [Katiyar and Meeran, 2007]. In an obesity-associated hepatoma model, IL-6 and TNF-alpha induce the development of cancer via activation of STAT3 pathway [Park et al. 2010].

Excess energy balance associated with the obesity may have an influence on tumour growth. Mouse tumour xenografts have decreased incidence and slower growth in mice fed a calorie restricted diet. Tumours which are resistant to dietary restriction have constitutive activation of the PI3K pathway [Kalaany and Sabatini, 2009].

The JAK–STAT pathway transmits information received from extracellular polypeptide signals through transmembrane receptors and is thought of as a signal transducing pathway for inflammatory cytokines. JAK–STAT activation stimulates cell proliferation, differentiation, cell migration and apoptosis [Quesnelle et al. 2007; Schindler and Darnell, 1995; Weerasinghe et al. 2007; Yue and Turkson, 2009]. Ligands which lead to activation of this pathway include many of the factors which are known to be upregulated in the obese state; IL-6, VEGF and leptin (37-40). These factors have been shown to be upregulated in visceral adipose tissue versus subcutaneous fat and serum concentrations of these ligands are increased in patients with visceral obesity versus lean controls [Lysaght et al. 2011]. Many of the tyrosine kinase receptors which are current or investigational therapeutic targets under trial at present such as IGF1R and EGFR signal through the STAT3 pathway. Aberrantly active STAT3 is also implicated in tumour formation [Spiotto and Chung, 2000; Yu et al. 2009; Yue and Turkson, 2009]. In contrast to the transient nature of Stat activation in normal cells, many human solid and haematological tumours harbour constitutive STAT3 activity [Yue and Turkson, 2009]. STAT3 promotes invasion and metastasis [Haura et al. 2005; Kortylewski et al. 2005; Turkson, 2004] and persistently active STAT3 functions as a master regulator of molecular and biological events that promote tumourigenesis [Siddiquee et al. 2007]. Extensive surveys of primary tumours and tumour cell lines indicate that inappropriate activation of specific STATS occur frequently in a wide variety of human cancers [Garcia and Jove, 1998]. Specific analysis of this pathway’s activity in tumours from obese patients, from obese mouse models or even in vitro cell line studies using conditioned media are lacking to date.

Conclusions

Obesity is a complex alteration in the normal metabolic and immunological environment. Altered adipokine production by adipose tissue, and in particular inflamed visceral adipose tissue, infiltrated with activated immune cells, may have an influence on the tumour and its microenvironment in a number of potential ways. First, systemic inflammatory cytokines are increased in obesity. This may affect the tumour either directly by stimulating the development of protumourigenic cancer cell properties by stimulating procarcinogenic signalling pathways. Systemic inflammation could equally alter the immune cells within the tumour’s micro-environment. Finally, systemic inflammation in obesity leads to circulating immune T cells with decreased antitumour activity, which may, in itself contribute to the relative tolerance of tumour cells. Uncovering the mechanisms underpinning this important health issue is the first step in uncovering new disease treatment and prevention paradigms.

Footnotes

Funding

This work is funded by an Irish Cancer Society research scholarship and an Irish Research Council for Science, Engineering and Technology scholarship.

Conflicting of interest statement

The authors have no conflicts of interest to declare.

References

Adams

Stroup

Gress

Adams

Calle

Smith

. (2009) Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring) 17: 796–802.

Aggarwal

Kunnumakkara

Harikumar

Gupta

Tharakan

Koca

. (2009) Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer. Ann NY Acad Sci 1171(1): 59–76.

Akiyama

Yoneda

Inamori

Iida

Endo

Hosono

. (2009) Visceral obesity and the risk of Barrett’s esophagus in Japanese patients with non-alcoholic fatty liver disease. BMC Gastroenterol 9: 56.

Algire

Amrein

Zakikhani

Panasci

Pollak

(2010) Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocrine-Related Cancer 17: 351–360.

Bassols

Ortega

Moreno-Navarrete

Peral

Ricart

Fernandez-Real

(2009) Study of the proinflammatory role of human differentiated omental adipocytes. J Cell Biochem 107: 1107–1117.

Bergman

Ader

(2000) Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 11: 351–356.

Bergström

Pisani

Tenet

Wolk

Adami

(2001) Overweight as an avoidable cause of cancer in Europe. Int J Cancer 91: 421–430.

Brakenhielm

Veitonmaki

Cao

Kihara

Matsuzawa

Zhivotovsky

. (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 101: 2476–2481.

Brown

Swanson

Gridley

Swanson

Schoenberg

Greenberg

. (1995) Adenocarcinoma of the esophagus: role of obesity and diet. J Natl Cancer Inst 87: 104–109.

10.

Calle

(2007) Obesity and cancer. BMJ 335: 1107–1108.

11.

Calle

Kaaks

(2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4: 579–591.

12.

Calle

Rodriguez

Walker-Thurmond

Thun

(2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348: 1625–1638.

13.

Chow

Blot

Vaughan

Risch

Gammon

Stanford

. (1998) Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 90: 150–155.

14.

Christou

Lieberman

Sampalis

(2008) Bariatric surgery reduces cancer risk in morbidly obese patients. Surg Obes Relat Dis 4: 691–695.

15.

Colangelo

Gapstur

Gann

Dyer

Liu

(2002) Colorectal cancer mortality and factors related to the insulin resistance syndrome. Cancer Epidemiol Biomarkers Prev 11: 385–391.

16.

Cook

Greenwood

Hardie

Wild

Forman

(2008) A systematic review and meta-analysis of the risk of increasing adiposity on Barrett’s esophagus. Am J Gastroenterol 103: 292–300.

17.

Corley

Kubo

Levin

Block

Habel

Zhao

. (2007a) Abdominal obesity and body mass index as risk factors for Barrett’s esophagus. Gastroenterology 133: 34–41; quiz 311.

18.

Corley

Kubo

Zhao

(2007b) Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms. Gut 56: 756–762.

19.

Creighton

Sada

Zhang

Tsimelzon

Wong

Dave

. (2012) A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat 132: 993–1000.

20.

Cummings

Foster

(2003) Ghrelin-leptin tango in body-weight regulation. Gastroenterology 124: 1532–1535.

21.

Curat

Miranville

Sengenes

Diehl

Tonus

Busse

. (2004) From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53: 1285–1292.

22.

Dai

Niu

(2007) Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol 13: 4199–4206.

23.

Das

(2001) Is obesity an inflammatory condition? Nutrition 17: 953–966.

24.

de Gonzalez

Sweetland

Spencer

. (2003) A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer 89: 519–523.

25.

Despres

Lemieux

(2006) Abdominal obesity and metabolic syndrome. Nature 444: 881–887.

26.

Despres

Moorjani

Lupien

Tremblay

Nadeau

Bouchard

(1990) Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 10: 497–511.

27.

Dieudonne

Bussiere

Dos Santos

Leneveu

Giudicelli

Pecquery

(2006) Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345: 271–279.

28.

Donohoe

Doyle

McGarrigle

Cathcart

Daly

O’Grady

. (2012) Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma. Br J Surg 99: 387–396.

29.

Donohoe

Doyle

Reynolds

(2011) Visceral adiposity, insulin resistance and cancer risk. Diabetol Metab Syndr 3: 12.

30.

Doyle

Donohoe

Finn

Howard

Lithander

Reynolds

. (2012) IGF-1 and its receptor in esophageal cancer: association with adenocarcinoma and visceral obesity. Am J Gastroenterol 107:196–204.

31.

Dunstan

Zimmet

Welborn

De Courten

Cameron

Sicree

. (2002) The rising prevalence of diabetes and impaired glucose tolerance: The Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 25: 829–834.

32.

Edelstein

Farrow

Bronner

Rosen

Vaughan

(2007) Central adiposity and risk of Barrett’s esophagus. Gastroenterology 133: 403–411.

33.

Engel

Chow

Vaughan

Gammon

Risch

Stanford

. (2003) Population attributable risks of esophageal and gastric cancers.J Natl Cancer Inst 95: 1404–1413.

34.

Engelman

(2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9: 550–562.

35.

Esposito

Giugliano

(2004) The metabolic syndrome and inflammation: association or causation? Nutr Metab Cardiovasc Dis 14: 228–232.

36.

Feldser

Agani

Iyer

Pak

Ferreira

Semenza

(1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59: 3915–3918.

37.

Ford

Zhao

Tsai

(2011) Trends in obesity and abdominal obesity among adults in the United States from 1999–2008. Int J Obes 35: 736–743.

38.

Fukuda

Hirota

Fan

Jung

Ellis

Semenza

(2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277: 38205–38211.

39.

World Cancer Research Fund (2007) Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective, Second Expert Report. Washington: American Institute for Cancer Research. Available at: http://www.dietandcancerreport.org/expert_report/

40.

Galic

Oakhill

Steinberg

(2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316: 129–139.

41.

Garcia

Jove

(1998) Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. J Biomed Sci 5(2): 79–85.

42.

Ghanim

Aljada

Hofmeyer

Syed

Mohanty

Dandona

(2004) Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110: 1564–1571.

43.

Giovannucci

Colditz

Stampfer

Willett

(1996) Physical activity, obesity, and risk of colorectal adenoma in women (United States). Cancer Causes and Control 7: 253–263.

44.

Greenberg

McDaniel

(2002) Identifying the links between obesity, insulin resistance and beta-cell function:potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest 32(Suppl. 3): 24–34.

45.

Guh

Zhang

Bansback

Amarsi

Birmingham

Anis

(2009) The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis. BMC Public Health 9(1): 88.

46.

Harriss

Atkinson

George

Cable

Reilly

Haboubi

. (2009) Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index. Colorectal Disease 11: 547–563.

47.

Haura

Turkson

Jove

(2005) Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Practice Oncol 2: 315–324.

48.

Healy

Ryan

Pidgeon

Ravi

Reynolds

(2010) Lack of differential pattern in central adiposity and metabolic syndrome in Barrett’s esophagus and gastroesophageal reflux disease. Dis Esophagus 23: 386–391.

49.

Howard

Beddy

Ennis

Keogan

Pidgeon

Reynolds

(2010) Associations between leptin and adiponectin receptor upregulation, visceral obesity and tumour stage in oesophageal and junctional adenocarcinoma. Br J Surg 97: 1020–1027.

50.

Huang

Han

Hui

(2010) MAPK signaling in inflammation-associated cancer development. Protein Cell 1: 218–226.

51.

Huffman

Augenlicht

Zhang

Lofrese

Atzmon

Chamberland

. (2013) Abdominal obesity, independent from caloric intake, accounts for the development of intestinal tumors in Apc1638N/+ female mice. Cancer Prev Res 6: 177–187.

52.

Jain

Bird

(2010) Elevated expression of tumor necrosis factor-alpha signaling molecules in colonic tumors of Zucker obese (fa/fa) rats. Int J Cancer 127: 2042–2050.

53.

Jing

Tweardy

(2005) Targeting Stat3 in cancer therapy. Anti-Cancer Drugs 16: 601–607.

54.

Kadowaki

Yamauchi

(2005) Adiponectin and adiponectin receptors. Endocr Rev 26: 439–451.

55.

Kalaany

Sabatini

(2009) Tumours with PI3K activation are resistant to dietary restriction. Nature 458: 725–731.

56.

Katiyar

Meeran

(2007) Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-[kappa]B signaling. Free Radical Biol Med 42: 299–310.

57.

Kershaw

Flier

(2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89: 2548–2556.

58.

Kim

Lee

(2009) An association between colonic adenoma and abdominal obesity: a cross-sectional study. BMC Gastroenterology 9(1): 4.

59.

Kissebah

Vydelingum

Murray

Evans

Kalkhoff

Adams

(1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54: 254–260.

60.

Kodelja

Muller

Tenorio

Schebesch

Orfanos

Goerdt

(1997) Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197: 478–493.

61.

Kono

Handa

Hayabuchi

Kiyohara

Inoue

Marugame

. (1999) Obesity, weight gain and risk of colon adenomas in Japanese men. Jpn J Cancer Res 90: 805–811.

62.

Kopfstein

Christofori

(2006) Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cell Mol Life Sci 63: 449–468.

63.

Kortylewski

Kujawski

Wang

Wei

Zhang

Pilon-Thomas

. (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11: 1314–1321.

64.

Lagergren

Bergstrom

Lindgren

Nyren

(1999a) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340: 825–831.

65.

Lagergren

Bergstrom

Nyren

(1999b) Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 130: 883–890.

66.

Larsson

Orsini

Wolk

(2007) Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer 120: 1993–1998.

67.

Larsson

Wolk

(2007a) Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr 86: 556–565.

68.

Larsson

Wolk

(2007b) Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer 96: 1457–1461.

69.

Larsson

Wolk

(2007c) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97: 1005–1008.

70.

Morris

Liu

Hassan

Day

Bondy

. (2009) Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 301: 2553–2562.

71.

Liu

Cheng

Roberts

Zhao

(2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8: 627–644.

72.

Lynch

Bell

Sordella

Gurubhagavatula

Okimoto

Brannigan

. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.

73.

Lysaght

van der Stok

Allott

Casey

Donohoe

Howard

. (2011) Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Lett 312: 62–72.

74.

Mendall

Patel

Asante

Ballam

Morris

Strachan

. (1997) Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart 78: 273–277.

75.

Moghaddam

Woodward

Huxley

(2007) Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev 16: 2533–2547.

76.

Moller

Flier

(1991) Insulin resistance—mechanisms, syndromes, and implications. N Engl J Med 325: 938–948.

77.

Moore

Bradlee

Singer

Splansky

Proctor

Ellison

. (2004) BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord 28: 559–567.

78.

Moore

Beltran

Carbajal

Strom

Traag

Hursting

. (2008) Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res 1: 65–76.

79.

Nedungadi

Clegg

(2009) Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. J Cardiovasc Transl Res 2: 321–327.

80.

Neels

Olefsky

(2006) Inflamed fat: what starts the fire? J Clin Invest 116: 33–35.

81.

Nieman

Henson

Nehlsen-Cannarella

Ekkens

Utter

Butterworth

. (1999) Influence of obesity on immune function. J Am Dietetic Assoc 99: 294–299.

82.

Nishimura

Manabe

Nagasaki

Eto

Yamashita

Ohsugi

. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914–920.

83.

Oberlin

Fellbaum

Eppler

(2009) Insulin-like growth factor I messenger RNA and protein are expressed in the human lymph node and distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and endothelial cells. Immunology 128: 342–350.

84.

Ogden

Carroll

Curtin

McDowell

Tabak

Flegal

(2006) Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 295: 1549–1555.

85.

Park

Lee

Ali

Holzer

. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140: 197–208.

86.

Pischon

Lahmann

Boeing

Friedenreich

Norat

Tjonneland

. (2006) body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 98: 920–931.

87.

Pollak

(2012) The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer 12: 159–169.

88.

Quesnelle

Boehm

Grandis

(2007) STAT-mediated EGFR signaling in cancer. J Cellular Biochem 102: 311–319.

89.

Renehan

Roberts

Dive

(2008a) Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem 114: 71–83.

90.

Renehan

Tyson

Egger

Heller

Zwahlen

(2008b) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371: 569–578.

91.

Roberts

Dive

Renehan

(2010) Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 61: 301–316.

92.

Ryan

Rowley

Fitzgerald

Ravi

Reynolds

(2006) Adenocarcinoma of the oesophagus and gastric cardia: male preponderance in association with obesity. Eur J Cancer 42: 1151–1158.

93.

Sartipy

Loskutoff

(2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci U S A 100: 7265–7270.

94.

Schaffler

Muller-Ladner

Scholmerich

Buchler

(2006) Role of adipose tissue as an inflammatory organ in human diseases. Endocr Rev 27: 449–467.

95.

Schaffler

Scholmerich

Buchler

(2005) Mechanisms of Disease: adipocytokines and visceral adipose tissue—emerging role in intestinal and mesenteric diseases. Nat Clin Pract Gastroenterol Hepatol 2: 103–111.

96.

Schindler

Darnell

Jr (1995) Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Ann Rev Biochem 64: 621–651.

97.

Schoen

Tangen

Kuller

Burke

Cushman

Tracy

. (1999) Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 91: 1147–1154.

98.

Sebolt-Leopold

Herrera

(2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4: 937–947.

99.

Serdula

Ivery

Coates

Freedman

Williamson

Byers

(1993) Do obese children become obese adults? A review of the literature. Prev Med 22: 167–177.

100.

Sharma

Katiyar

(2010) Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin. Toxicol Appl Pharmacol 244: 328–335.

101.

Shoelson

Lee

Goldfine

(2006) Inflammation and insulin resistance. J Clin Invest 116: 1793–1801.

102.

Siddiquee

Zhang

Guida

Blaskovich

Greedy

Lawrence

. (2007) Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A 104: 7391–7396.

103.

Sjostrom

Gummesson

Sjostrom

Narbro

Peltonen

Wedel

. (2009) Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 10: 653–662.

104.

Snijder

Dam

Visser

Seidell

(2006) What aspects of body fat are particularly hazardous and how do we measure them? Int J Epidemiol 35: 83–92.

105.

Spiotto

Chung

(2000) STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 42: 186–195.

106.

Steffen

Schulze

Pischon

Dietrich

Molina

Chirlaque

. (2009) Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 18: 2079–2089.

107.

Sunderkotter

Steinbrink

Goebeler

Bhardwaj

Sorg

(1994) Macrophages and angiogenesis. J Leukoc Biol 55: 410–422.

108.

Taron

Ichinose

Rosell

Mok

Massuti

Zamora

. (2005) Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 11: 5878–5885.

109.

Trayhurn

Wood

(2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92: 347–355.

110.

Trevisan

Liu

Muti

Misciagna

Menotti

Fucci

(2001) Markers of insulin resistance and colorectal cancer mortality. Cancer Epidemiol Biomarkers Prev 10: 937–941.

111.

Troiano

Flegal

(1999) Overweight prevalence among youth in the United States: why so many different numbers? Int J Obes Relat Metab Disord 23(Suppl. 2): S22–S27.

112.

Turkson

(2004) STAT proteins as novel targets for cancer drug discovery. Expert opinion on therapeutic targets 8: 409–422.

113.

van Kruijsdijk

van der Wall

Visseren

. (2009) Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 18: 2569–2578.

114.

Vaughan

Davis

Kristal

Thomas

(1995) Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 4: 85–92.

115.

Vohl

Sladek

Robitaille

Gurd

Marceau

Richard

. (2004) A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes Res 12: 1217–1222.

116.

Wajchenberg

(2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21: 697–738.

117.

Wang

Jacobs

Patel

Rodriguez

McCullough

Thun

. (2008) A prospective study of waist circumference and body mass index in relation to colorectal cancer incidence. Cancer Causes Control 19: 783–792.

118.

Wang

Lam

(2007) Adiponectin as a negative regulator in obesity-related mammary carcinogenesis. Cell Res 17: 280–282.

119.

Weerasinghe

Garcia

G.E.

Zhu

Yuan

Feng

Mao

. (2007) Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. Int J Oncol 31: 129–136.

120.

Weisberg

McCann

Desai

Rosenbaum

Leibel

Ferrante

Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796–1808.

121.

Wellen

Hotamisligil

(2003) Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 112: 1785–1788.

122.

WHO (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894: i–xii, 1–253.

123.

Barnes

Yang

Tan

Yang

Chou

. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821–1830.

124.

Ya-Yu

Shih-Yi

Wen-An

Pi-Hwa

Wayne Huey-Herng

(2005) Association between adenomas of rectosigmoid colon and metabolic syndrome features in a Chinese population. J Gastroenterol Hepatol 20: 1410–1415.

125.

Yamauchi

Kamon

Waki

Terauchi

Kubota

Hara

. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7: 941–946.

126.

Pardoll

Jove

(2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9: 798–809.

127.

Yue

Turkson

(2009) Targeting STAT3 in cancer: how successful are we? Exp Opin Invest Drugs 18: 45–56.

128.

Zaninotto

Wardle

Stamatakis

Mindell

Head

(2006) Forecasting Obesity to 2010. National Centre for Social research, Department of Health, London. Available at: http://www.erpho.org.uk/Download/Public/15199/1/ForecastingObesityTo2010.pdf.

The role of obesity in gastrointestinal cancer: evidence and opinion

Abstract

Keywords

The obesity problem

Obesity and cancer: the epidemiological association

Mechanisms underpinning the association between obesity

Obesity is a state of chronic systemic inflammation

The obese state represents an altered immunological milieu

Adipokine levels in obese individuals

Signalling pathways and alterations in obesity

Conclusions

Footnotes

Funding

Conflicting of interest statement

References