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The recent worldwide estimates indicate that 400 million individuals aged ≥ 15 years are obese, reflected clinically by a surrogate measure of body mass index (BMI) ≥ 30.0kg/m2 (World Health Organisation). The continuously increasing number of individuals with obesity is of major public health concern, not only because excess body weight increases the risk of chronic diseases such as type 2 diabetes, hypertension, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and cardiovascular disease, but also as it is a recognised risk factor for several solid tumours and haematological malignancies (Pischon et al. 2008; Cleary and Grossmann, 2009; Rehenan et al. 2008; Deslypere, 1995). Obesity can also have a negative impact on the prognosis for some types of cancer (Calle et al. 2003; Parekh et al. 2009; LeRoith et al. 2008). Obesity is a condition with complex pathophysiology, often associated with chronic hyperinsulinaemia and insulin resistance that may eventually lead to type 2 diabetes mellitus, which is also linked with increased risk of several cancers. This prompted the speculations that the systems regulating insulin sensitivity and energy balance may have an effect on cancer-related processes, such as tumour progression. Nevertheless, despite convincing epidemiological data, the biological aspects linking obesity and type 2 diabetes mellitus with cancer are still not fully understood and are a subject of intense research efforts.
Epidemiology - an overview
A systematic review and meta-analysis of prospective observational studies (221 datasets) revealed that increased BMI is associated with increased risk of several solid tumours, including endometrial, colorectal, post-menopausal breast, prostate, renal and thyroid cancer, malignant melanoma and esophageal carcinoma (Rehenen et al. 2008). Moreover, several large cohort studies and meta-analyses indicate that excess body weight increases the risk for several haematological malignancies, including leukaemia, non-Hodgkin's lymphoma (particularly diffuse large B-cell lymphoma) and multiple myeloma (Rehenen et al. 2008; Lichtman, 2010). Compared to BMI, body fat distribution can be an even better predictor of risk for certain cancers, e.g. post-menopausal breast cancer (Lahmann et al. 2003). Similarly, type 2 diabetes may increase risk and mortality of several cancers, including breast cancer (Schrauder et al. 2010; Erickson et al. 2010), and pancreatic cancer (Bao et al. 2010). The association between BMI and risk of cancer appears to be affected by factors associated with sex- and cancer-site, and is noted consistently across geographic populations (Renehan et al. 2008). Taking into account the consistency from epidemiological findings and the long period between the measurement of BMI and occurrence of cancer, it is suggested that the relationship is of causal nature. Thus, intense research efforts are directed towards analysing the biological plausibility of the relationship between obesity and cancer.
Adipose tissue: an active endocrine organ
According to WHO classification, obesity is defined by BMI greater than 30kg/m2. However, it is body fat distribution rather than the fat found in adipose tissue that is of great importance in obesity-related disorders. An excess of intra-abdominal fat, but not subcutaneous fat, is associated with increased risk of type 2 diabetes mellitus, and cardiovascular disease. It is thus postulated that metabolic products, hormones and/or proteins released from the visceral adipose tissue may directly affect sensitivity of peripheral tissues to insulin, metabolism of lipoproteins, as well as blood pressure. The white adipose tissue which is the site of energy storage in mammals contains not only adipocytes and pre-adipocytes, but also non-fat cells such as endothelial cells, fibroblasts, and immune cells such as leukocytes and macrophages. It has been recognised that adipose tissue does not function simply as the storage of fat, but is also an active secretory endocrine organ (Berg and Scherer, 2005; Tilg and Moschen, 2006). Moreover, visceral adipose tissue secretes significantly more proteins, including angiogenesis factors, than subcutaneous adipose tissue (Hocking et al. 2010). The action of adipose tissue-derived hormones, proteins and/or chemokines at different sites may influence various physiological processes, and affect tumorigenesis either independently or through abnormal insulin signalling.
Cancer: a general overview of molecular pathophysiology
Cancer is a disease characterised by increasing cell survival and proliferation, and often associated with migration of cancer cells and invasion of other tissues/organs. The molecular aspects of cancer have been summarised in several seminal review papers (Hanahan and Weinberg, 2000; Lazebnik 2010), and include avoidance of apoptosis, limitless proliferation, induction of angiogenesis, independence of growth factors, and ability to metastasise (Fig. 1A). Inhibition of apoptotic cell death is considered to be particularly significant in tumour development, as it can protect cancer cells from the action of intracellular pro-apoptotic proteins (e.g. in response to oncogene activation), immune system, or from chemotherapy-induced cell death. Apoptosis is a highly regulated process which causes cellular death that in general occurs through the mitochondrial (intrinsic) pathway or through the death receptor (extrinsic) pathway (Fig. 1B).
Figure 1 Inhibition of apoptosis and increased cell proliferation are among the main characteristics of cancer.
The characteristic features of cancer cells and tumours that allow uncontrollable neoplastic growth [based on Hanahan and Weinberg, 2000]. B) Apoptosis is triggered by the death receptor or the mitochondrial pathway. Caspase 8 (casp8), activated by death receptors, cleaves the BH3-only protein Bid, producing truncated Bid (tBid) which links the extrinsic pathway with the mitochondrial pathway. Mitochondria are sentinels of multiple stress signals, many of which affect the Bcl-2 family of proteins that consists of anti-apoptotic as well as pro-apoptotic (e.g. Bax, Bak, BH3-only proteins such as Bid or Bad) members. The activation of pro-apoptotic Bcl-2 proteins leads to mitochondrial outer membrane permeabilization (MOMP), and release of cytochrome c (Cyt c) into the cytosol. Cytochrome c initiates the formation of a multiprotein complex (the apoptotsome) on which caspase 9 is activated. Activation of caspase 3 follows, culminating in execution of apoptotic cell death [based on Chipuk et al. 2010; Cory and Adams, 2002].
Anti-apoptotic Bcl-2 proteins
Evasion of apoptosis
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Limitless replicative potential
Tissue invasion and metastasis
The mitochondrial pathway is regulated by the family of Bcl-2 proteins, which consists of both pro- and anti-apoptotic members (Chipuk et al. 2010; Cory and Adams, 2002). In cancer cells the balance of Bcl-2 proteins is shifted towards overexpression of the anti-apoptotic members (Chipuk et al. 2010). Other mechanisms leading to inhibition of apoptosis in cancer cells include abnormal functioning or loss of tumour suppressor protein p53, or pro-survival kinase signalling pathways such as PI3-K/Akt/mTOR (Vousden and lane, 2007; Chen et al. 2005). The role of DNA damage and inflammation in development and progression of cancer has also been firmly established (Halazonetis et al. 2008; Coussens and Werb, 2002).
As tumourigenesis is a multi-stage process regulated by complex signalling pathways, it is possible that obesity-associated abnormalities affect different aspects of cancer development. Firstly, metabolic, endocrinological and immunological changes associated with excess body weight could increase the rate of DNA damage and cause dysfunction to genes, DNA repair, cell proliferation and death, promoting neoplastic transformation. In addition, the physiological changes associated with obesity could favour the expansion of pre-neoplastic cells that would otherwise remain in dormant state.
Candidate mechanisms linked to insulin resistance and energy balance
The most studied systems that have been proposed to link obesity with cancer are involved in regulation of insulin sensitivity and energy balance, and include: insulin and insulin-like growth factors (IGFs), sex hormones, and adipokines.
Insulin and insulin-like growth factor-I (IGF-I) axis
It is well recognized that BMI positively correlates with circulating insulin levels, and many obese individuals develop insulin resistance, defined as a state of diminished responsiveness of tissues to the physiological levels of insulin (Calle and Kaaks, 2004; Walker, 1995).
First suggestions that hyperinsulinemia may contribute to tumorigenesis due to the growth-promoting effects of elevated serum insulin levels were published in mid 1990s (McKeown-Eyssen, 1994; Giovannucci, 1995). Since then further clinical and epidemiological evidence has accumulated to support the theory that hyperinsulinemia and insulin resistance correlate with greater risk for several malignancies, and in some cases with poor prognosis and increased mortality (Hursting and Berger, 2010). For example, high levels of serum C-peptide (a marker for insulin secretion) appear to be associated with increased risk of post-menopausal breast cancer, as well ascolorectal and endometrial cancer (Renehan et al. 2008). This is in agreement with findings on cancers associated with obesity (Renehan et al. 2008). Furthermore, both obesity and hyperinsulinemia are linked to breast cancer according to recent study involving over 800 incident breast cancer subjects (Gunter et al. 2009).
Figure 2 Proposed role of insulin and IGF-IR axis in tumour development. A) Prolonged hyperinsulinemia associated with obesity reduces IGFBP-1 and -2 levels, and increases hepatic production of IGF-I. An increase in free IGF-I leads to enhanced activation of IGF-I receptor intracellular signalling that protects from apoptosis and enhances cell proliferation [Adapted from Roberts et al. 2010]. B) IGF-IR is a transmembrane ligand-activated tyrosine kinase receptor. Upon ligand binding the receptor undergoes autophosphorylation, and activation. Active IGF-IR phosphorylates associated substrate proteins, triggering intracellular signalling cascades. The main pathways involved in regulation of apoptosis and proliferation are PI3K/Akt, and ERK. Both pathways exert some of their action in the cytosol, for example by activating mTOR or interacting with the Bcl-2 family of proteins that controls the mitochondrial integrity. In the nucleus, ERK and Akt modulate expression of genes regulating cell survival (e.g. NFκB, Bcl-2, Bcl-Xl), growth and proliferation [based on Gallagher and LeRoith, 2010].
Cell proliferation ↑
Excess body weight
Free IGF-I ↑
Anti-apoptotic Bcl-2 proteins
Anti-apoptotic Bcl-2 proteins
The simplified insulin-IGF-cancer hypothesis, as depicted in Figure 2, suggests that excess body weight leads to prolonged hyperinsulinemia, which in turn results in increased hepatic production of IGF-I (insulin-like growth factor I), as well as reduced levels of IGF binding proteins (IGFBP)-1 and IGFBP-2 (Fig. 2A). IGF-I that is normally bound to IGFBPs is thus freed, and able to apply its action on target cells (Fig. 2A) (Gallagher and LeRoith, 2010). In support of this hypothesis, elevated serum levels of IGF-I are consistently found in obese individuals (Frystyk, 2004). Insulin and IGF-I bind to and activate insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively, as well as hybrid receptors composed of IGF-IR αβ and IR αβ complexes (Fig. 2A) (Soos et al. 1990). Activation of IGF-IR triggers intracellular signalling cascades, including extracellular-signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3-K) pathways, both of which are involved in regulation of cell growth and proliferation, as well as inhibition of apoptosis (Fig. 2B). Moreover, PI3-K/Akt pathway activates mammalian target of rapamycin (mTOR), which in turn not only stimulates specific metabolic pathways, but also transcriptionally regulates sterol regulatory element-binding protein (SREBP1 and SREBP2) and Smad that promote cell proliferation (Düvel et al. 2010). In addition to anti-apoptotic and proliferation stimulating action of IGF-I, it has also been shown to promote tumour-related lymphangiogenesis and tumour invasion, potentially through its effects on activity of integrin-associated proteins such as FAK, p130, Cas or paxillin (Guvakova, 2007).
For long it has been proposed that proliferation effects of insulin are mediated predominantly through IGF-I receptors, and multiple in vitro and in vivo studies have firmly implicated the IGF system in tumour initiation and progression. Recent findings suggest, however, that both IR and IGF-IR can convey pro-tumorigenic signals (Ulanet et al. 2010).
Increased BMI is associated with increased risk for sex hormone-sensitive cancers, such as post-menopausal breast cancer, endometrial and prostate cancers (Rehenen et al. 2008). This may be, at least in part, due to the ability of adipose tissue to regulate biosynthesis of steroid hormones. In postmenopausal women increased BMI is associated with increased levels of estrone, estradiol and free estradiol (Key et al. 2003), and adipose tissue appears to be the main source of oestrogen (Cleary and Grossmann, 2009). The higher rate of oestrogen biosynthesis is caused by an increase in the activity of enzymatic complex referred to as aromatase, found in adipose tissue in the breast and in tumours (Miller, 2006). Moreover, adipocytes secrete TNF-α and IL-6, which can enhance production of aromatase and thus contribute to elevated levels of oestrogen (Purohit et al. 2002). Oestrogen has important role in regulating energy homeostasis, and acts to suppress energy intake, enhance energy expenditure, as well as improve insulin secretion and sensitivity (Mauvais-Jarvis, 2010). Despite positive impact of oestrogens on metabolic homeostasis, local increase in oestrogen levels may have cancer-promoting effects that in some cases may be intermingled with the insulin/IGF-I axis. The tumorigenic role of oestrogen has been well documented using in vitro and in vivo models, and involves different signalling and transcriptional activities of oestrogen receptor (ER) α and ERβ (Chang et al. 2006). The association between excess body weight and postmenopausal breast cancer is almost entirely attributable to increased serum levels of estradiol, whereas in younger women obesity-associated increase in serum levels of testosterone may potentially contribute to increased risk of breast cancer (Key et al. 2003). Importantly, the feedback relationships between IGF-I, andiponectin and oestrogen appear to be important in determining the overall risk of breast cancer (Roberts et al. 2010), while in endometrial cancer the proliferative and anti-apoptotic action of estradiol is largely mediated by an increase in local synthesis of IGF-I (Roberts et al. 2010).
Adipocytes secrete over 50 polypeptide hormones, referred to as adipokines. The most abundant of adipokines, adiponectin, is involved in regulation of carbohydrate and lipid metabolism, as well as insulin sensitivity, and is the most widely studied in relation to cancer (Barb et al. 2007). Adiponectin is an important insulin-sensitising agent, secretion of which is inhibited by insulin as well as oestrogen. Epidemiological data strongly suggest inverse association between serum levels of adiponectin and endometrial cancer, independently of other obesity-related factors (Petridou et al. 2003; Dal Maso et al. 2004; Cust et al. 2007), as well as breast cancer (Miyoshi et al. 2003; Mantzoros et al. 2004), prostate (Goktas et al. 2005) and colorectal (Wei et al. 2005) cancers. Moreover, serum levels of adiponectin negatively correlate with BMI, which overall suggests that adiponectin may be a biological link between the obesity and cancer (Barb et al. 2007). On the molecular level, adiponectin can inhibit cancer cell proliferation and induce apoptosis by activating AMP kinase, increasing Bax/Bcl-2 ratio and enhancing p53 expression (Dos Santos et al. 2008; Dieudonne et al. 2006, Arditi et al. 2007). Adiponectin has also been shown to exert proangigenic effects. Studies in animal models revealed that adiponectin deficiency can inhibit development and progression of primary tumours due to reduced tumour vascularisation (Denzel et al. 2009). Thus, the effects of adiponectin levels on cancer development are complex and may well depend on the stage of tumorigenesis.
Obesity is associated with macrophage access into adipose tissue, stimulated by activation of immune system, and resulting in a chronic low-grade inflammatory response (Federico et al. 2010). Importantly, based on epidemiological studies as well as animal models, the inflammation of adipose tissue in obesity is strongly linked to pathogenesis of insulin resistance (Hu et al. 2003). Chronic inflammation of adipose tissue is characterised by abnormal cytokine production (e.g. IL-6, IL-1β, TNF-α, C-reactive protein), activation of proinflammatory pathways such as c-Jun NH2-therminal kinase (JNK) and IκB kinase-β (IKK-β), decreased T- and B-cell function, as well as increased monocyte and granulocyte phagocytosis (Niemann et al. 1999). Moreover, recent studies suggest that obesity promotes expansion of IL-17-secreting T lymphocytes, which potentially may be involved in pathogenesis of malignancy (Ahmed and Gaffen, 2010; Gislette and Chen, 2010). There is also convincing evidence to support the role of inflammation in tumorigenesis (Coussens and Werb, 2002), and so by extrapolation obesity-related low-grade inflammation might contribute to both insulin resistance and cancer development or progression. At present, it still remains to be determined whether macrophage infiltration and low-grade inflammation typically accompanying obesity can directly contribute to an increased risk for cancer (Roberts et al. 2010).
Implications for therapy
Understanding the molecular links between obesity and cancer contributes to the development of novel therapeutic strategies. For example, monoclonal antibodies and small molecule inhibitors that block IGF-IR signalling have been studied extensively in preclinical cancer models (e.g. Wang et al. 2006, Bortrum et al. 2003, Ji et al. 2007), and some are currently in phase II clinical testing for several human malignancies, including solid as well as haematological tumours (Scartozzi et al. 2010). Metformin, commonly used to treat insulin resistance, is also proving effective in inhibition of breast cancer cell proliferation, invasion and angiogenesis (Wysocki and Wierusz-Wysocka, 2010). The anti-cancer properties of metformin are most apparent in patients with type 2 diabetes (Yang et al. 2010).
Obesity is associated with dysfunction of several biological systems and a number of circulating factors that are of clear relevance to cancer development and/or progression. Most of the supporting evidence for the link between obesity and cancer results from epidemiological studies, as well as in vitro and in vivo cancer models, linking obesity-related factors directly, or indirectly, with the process of tumorigenesis. As mammary gland is largely composed of adipocytes, breast cancer is a determining example of the large number of, and complex relationship between, the obesity-associated factors, acting independently as well as in concert to promote neoplastic growth. Adipose tissue hypoxia is critical for development of insulin resistance, low-grade chronic inflammation, as well as reduced adiponectin and increased leptin secretion, and thus it is hypothesized that obesity-related hypoxia is the key factor linking excess weight with tumorigenesis (Roberts et al. 2010). Thus further studies are required to access the plausibility of this hypothesis.