The effect of being overweight and obese on the risk of cancer is at least twice as large as previously thought according to new findings by an international research team which included University of Bristol academics.
The study published in the International Journal of Epidemiology was led by the International Agency for Research on Cancer (IARC) and involved researchers from Bristol Medical School.
The team conducted genetic analyses on eight common obesity-related cancer types.
They compared the genetic Mendelian randomization estimates of the association between body mass index (BMI) and cancer risk with the estimates from classical cohort studies.
According to the results of this new analysis, the proportion of cancers attributable to overweight and obesity is, in fact, substantially higher.
Richard Martin, Professor of Clinical Epidemiology at the University of Bristol Medical School, said: “The importance of these analyses is that they suggest that the effect of being overweight on cancer risk has been underestimated in the past and that obesity plays an even more important role in cancer than previously suggested.”
The current impact of obesity on public health is a headline concern worldwide, especially since obesity is a significant risk factor for several types of cancer. Obesity is characterized by an excess of body fat considered to be harmful to health and defined by the World Health Organisation as a body mass index (BMI; body weight [kg]/height [m2]) >30 kg/m2 (WHO, 2016) (class 1, 30–35, class 35–40, class 3 > 40) with normal values considered as 18.5–24.9 kg/m2 and overweight as intermediate values of 25–29.9 kg/m2. The term ‘lean’ is occasionally used to refer to weights below 18.5 kg/m2.
By these criteria around two-thirds of adults aged over 20 years in the USA are currently overweight with a prevalence of obesity of approximately 35% (Ogden et al., 2012), predicted to reach 42% by 2030 in people over 18 years (Finkelstein et al., 2012).
The main driver for obesity is believed to be an overall rise in caloric intake (Swinburn et al., 2009) with a shift towards snacking patterns of eating and increased consumption of high carbohydrate beverages and dietary fat. Low levels of physical activity increase the problem (Cameron et al., 2003) with a significant but poorly understood role of genetic factors (Thorleifsson et al., 2009).
Significant consequences of obesity include the medical, economic and social burdens of obesity-related comorbidities such as coronary heart disease, type-2 diabetes mellitus, respiratory disease and cancer (Renehan et al., 2008).
Many of the global concerns around the links between environmental factors and diet, nutrition, obesity and cancer are addressed by the World Cancer Research Fund (WCRF) and their various publications (http://www.wcrf.org/int/policy/our-publications).Go to:
Obesity and Cancer
Tumor development involves a local microenvironment which promotes cell proliferation, partly through release of mitogenic signals, and induces cell survival mechanisms as well as the induction of tolerance in cytotoxic host T cells (Hanahan and Weinberg, 2011; Prendergast et al., 2010). Parkin and Boyd (2011) estimated that 5.5% of cancer cases in the UK were related to overweight and obesity while others have claimed that the relative risk of mortality from cancer, attributable to obesity, was approximately 14.2% in men and 19.8% in women (Calle et al., 2003).
The association between obesity and cancer is quite secure in human populations (Arslan et al., 2009; Pischon et al., 2008; Xu et al., 2003) especially with respect to tumors of the gastrointestinal (GI) tract (Zeng and Lazarova, 2012; Zeng et al., 2014) where being overweight carries a 1.5–2.4-fold increase in cancer risk (Moore et al., 2005).
The link has also been supported by animal experiments in which obesity and cancer have been modified by dietary means (Nogueira et al., 2012a, Nogueira et al., 2012b). Several studies have attempted to define the types of cancer most highly associated with obesity, which include breast cancer in postmenopausal women, colon cancer (especially in men), endometrial, esophageal adenocarcinoma, gall bladder and renal cancers (Bhaskaran et al., 2014; Price et al., 2012; Renehan et al., 2008).
Awareness of the role of lifestyle factors in the relationship between obesity and cancer is gaining prominence and will be addressed in a later section. For example, high red and processed meat consumption has been identified as a risk factor for colorectal cancer (Alexander et al., 2011; Huxley et al., 2009; Magalhaes et al., 2012; Norat et al., 2005) and with an increased risk of obesity (Wang and Beydoun, 2009).
A role for adipose tissue is also relevant in the case of breast cancer, where a strong association exists between the amount of mammary adipose tissue and collagen (broadly equating with overall breast size), breast cell density and lifetime risk for mammary cancer (Boyd et al., 2007; DeFilippis et al., 2012).
This may be related to the inverse expression of CD36, a common membrane protein which plays a role in cell development and intercellular interactions. Lower levels of CD36 in breast tissue lead to an increase in collagen deposition at the expense of adipose tissue, which declines in quantity.
Further factors influencing breast cancer development via obesity and breast adiposity have included the possible influence of estrogens produced in adipose tissue. These steroids can promote carcinogenesis and add to the lifetime total of estrogen stimulation from oral contraceptives, hormone replacement therapy, and pregnancies (Gerard and Brown, 2017).
Adipose tissue is an important site of insulin activity, promoting triglyceride storage and inhibiting lipolysis (Choi et al., 2010). There is a strong positive relationship between fasting insulin levels and postmenopausal cancer risk, specifically in non-users of hormone therapy (Gunter et al., 2009) consistent with the view that postmenopausal breast cancer is analogous to obesity-associated cancer resulting from insulin resistance (Bhaskaran et al., 2014; Renehan et al., 2008). Insulin resistance is a feature of obese individuals, accompanied by a high circulating insulin level which is a well-established risk factor for cancer (Kim et al., 2004; Goodwin et al., 2002; Hsing et al., 2001) and which is associated with marked changes in the levels of inflammatory markers (Lee and Lee, 2014).
In a sample of 208 healthy non-obese volunteers, insulin sensitivity was correlated with cancer development over a 6-year period (Facchini et al., 2001). The insulin resistance associated with obesity may be symptomatic of a more profound dysfunction of the insulin/insulin-like growth factor-1 (IGF-1) axis (Kim et al., 2004; Cohen and LeRoith, 2012). Obesity-related insulin resistance and hyperinsulinemia are associated with elevated blood levels of unbound, but not total, IGF-1 protein (Frystyk et al., 1995; Nam et al., 1997) with activation of the insulin and IGF-1 receptors (IGF-1R) triggering transduction pathways which promote tumor growth (Kulik et al., 1997; Parrizas et al., 1997). Obesity-associated insulin resistance gives rise to increased free IGF-1 levels in the postprandial state whereas a reduction of free IGF-1 is observed in lean insulin-sensitive subjects (Ricart and Fernández-Real, 2001).
High levels of insulin could dysregulate IGF-1 signalling by their ability to reduce expression of the hepatic IGF Binding Proteins (IGFBP) (Nam et al., 1997) resulting in increased levels of free IGF. Whether the chronic pattern of postprandial IGF-1 levels is an important factor in the relevance of this protein to obesity remains unresolved, but it could clearly contribute to the obesogenic (and diabetogenic) propensity of modern ‘snacking’ behavior with the frequent consumption of small quantities of foodstuffs, especially those solid and liquid varieties providing high doses of carbohydrate.
Colorectal cancer risk has been associated with increased levels of circulating IGF-1 in men (Ma et al., 1999) although Wolpin et al. (2009) found no link between IGF-1 and colorectal-cancer specific mortality. In addition, a case-control study discovered no association between IGF-1 and premenopausal or postmenopausal breast cancer (Petridou et al., 2000). However, the relative amounts of bound and free IGF present were not clear.
Both receptors interact with the intracellular insulin receptor substrate 1, which subsequently promotes the phosphoinositide 3-kinase (PI3 kinase)/protein kinase B (Akt) cascade (Myers et al., 1994). This pathway ultimately inhibits programmed cell death (Datta et al., 1997; Kulik et al., 1997). Upon insulin and IGF-1R activation, the intracellular protein Ras stimulates the mitogen-activated protein kinase (MAPK) pathway, which also plays a vital role in cell proliferation and inhibition of apoptosis (Parrizas et al., 1997; Menu et al., 2004) (Fig. 1).
More information: Daniela Mariosa et al. Commentary: What can Mendelian randomization tell us about causes of cancer?, International Journal of Epidemiology (2019). DOI: 10.1093/ije/dyz151
Journal information: International Journal of Epidemiology
Provided by University of Bristol