Obesity: a perfect storm for carcinogenesis

Abstract

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.

Keywords: Adiposity; BMI; Cancer; Carcinogenesis; Hallmarks of cancer; Obesity.

Fig. 1

How obesity can influence the hallmarks of cancer, enabling characteristics and emerging hallmarks. A circos plot illustrating the links between obesity-related factors and the hallmarks of cancer (classical and emerging) and enabling characteristics. Obesity-related factors are located in the top half of the plot, while hallmarks of cancer and enabling characteristics are found in the bottom half. In the top half of the plot, the outer coloured blocks denote the factors that are affected by obesity with one colour per factor (e.g. cyan for adiponectin). The ten groupings in Table 1 are indicated by the inner semi-circle in the top half of the plot (e.g. adiponectin, leptin and resistin are all classified as adipokines in Table 1 and indicated by an indigo bar in the inner semi-circle). Lines between the bottom half and top half highlight obesity-related factors and their relationship to particular hallmarks/characteristics. The colour of the lines relates to the relevant hallmark/characteristic (e.g. green for sustaining proliferative signaling). Factors can influence several hallmarks. The basis for linking each factor to a particular hallmark/characteristic is discussed in the main text, while Table 1 gives the direction of change of each factor in obesity as well as an exemplar reference

Fig. 2

Leptin/adiponectin balance in obesity. Leptin and adiponectin are two adipokines produced by adipose tissue. Leptin levels rise in obesity, while adiponectin falls. Leptin binds to a growth factor receptor at the cell surface, and promotes cell proliferation/opposes cell death by a variety of mechanisms. These include promoting cell growth (via stimulation of mTOR), angiogenesis and metastasis, while at the same time inhibiting antitumour mechanisms such as apoptosis and immune surveillance. Overall, therefore, the actions of leptin are pro-tumorigenic. Adiponectin, in contrast, binds to a G-protein coupled receptor at the cell surface, and broadly opposes these actions of leptin, by activating kinases such as AMP kinase (which decreases mTOR activity) and protein kinase A (which decreases angiogenesis). Normally the actions of these two hormones are balanced, to maintain cell proliferation at an appropriate rate, but in obesity leptin concentrations rise, and adiponectin falls, promoting a tumorigenic environment

Fig. 3

Major factors that can promote cellular invasion and metastasis in obesity. Migration, invasion and metastasis are influenced by a number of different factors in obesity. At the primary tumour site, leptin, IL-6 and TGFβ can promote epithelial-mesenchymal transition (EMT). Combining this with systemic hyperinsulinemia, exosomal influences and cross-feeding by nearby adipocytes cellular migration can be encouraged. Cells escape through the blood and lymphatic vessels, increased in number by elevated factors such as VEGF-A and ANGPTL2 (other factors reviewed in the ‘Inducing angiogenesis’ section). Furthermore, the physiological state of obesity acts to prime distant niches for metastasis through various mechanisms, for instance the induction of CCL5 expression

Fig. 4

Notable effects of obesity on immunosuppression and inflammation. Cells relating to immune surveillance of cancer, raised in obese adipose tissue, are shown (Th1/Th17 and CD8 + T cells, dendritic cells, pro-inflammatory macrophages and iNKT cells). Suppression is shown as black blunted lines. Circulating cytokines, IL-6 (acts on dendritic, CD8 + T cells and macrophages) and IL-18 (acts on iNKT cells), are major mediators of immune suppression, but other growth factors/cells can suppress immune responses in dendritic cells (VEGF), macrophages (PlGF), Th1/Th17 cells (TGFβ, MDSC) and CD8 + T cells (MDSC). Small molecule effectors may also be involved-adenosine and kynurenine dampen the immune response in Th1/Th17 cells while lactate suppresses actions of iNKT cells. Simultaneously these cells, notably the pro-inflammatory macrophages and CD8 + T cells, release cytokines IL-6 and IL-18 (red arrows), resulting in a complex feedback system. They are stimulated to do so by extracellular mediators such as fatty acids (raised in obesity), DAMPS (from dying adipocytes in ‘crown-like’ structures), IL-1β and TNFα, via NF-κB, the predominant intracellular coordinator of inflammation