Obesity and cancer development: causal associations

Since obesity is now an established risk factor for cancer development, the next question is how this may be exploited in order to uncover mechanisms underpinning the link between obesity and carcinogenesis, thus opening future avenues for cancer prevention and therapy.


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Inflammation

Excess adipose tissue results in elevated levels of proinflammatory adipokines, resulting in an imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms, leading to persistent low-grade inflammation.31–33

Adipose tissue, through the systemic alterations associated with obesity, may support the development of malignant potential in susceptible cells through supporting the other malignant processes within cancer cells, such as invasion and metastases, evasion of apoptosis, and promotion of angiogenesis and systemic inflammation.

Inflammation provides the selective pressure that may drive the accumulation of mutations and results in poor immune surveillance of tumors once they develop.Cytokines secreted by adipose tissue include the following 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).

Some of these cytokines have an anti-inflammatory effect (IL-10 and IL-1Ra), but the majority are proinflammatory, and overall markers of systemic inflammation, such as C-reactive protein (CRP), are increased in the obese state.34 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.35–37 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.38–41

Adipose tissue in obese people is infiltrated with macrophages, and the number of macrophages correlates with the degree of adiposity.42In obesity-associated systemic inflammation, there are increased circulating factors that activate the cells of the tumor microenvironment.

The cells in the tumor microenvironment (including fibroblasts, neutrophils, T-cells, macrophages, and mast cells) secrete factors which support proliferation and invasion of epithelium cells, which under normal circumstances would result in wound healing, but in the presence of mutated cancer cells, promotes their further proliferation and invasion.

Animal models provide some evidence supporting these mechanisms. Obese rat models have increased inflammatory transcription factor expression (TNF-α and NFκB) in their tumor cells indicating activation of the tumor cells themselves to produce inflammatory cytokines which suppress the surrounding immune cells.43

Furthermore, there is emerging evidence that adipose tissue stromal cells may be a source of stromal cells in tumor microenvironments.44 Early adipocyte precursor stem cells can differentiate into stromal cells.45 In animal models of obesity, adipose stromal cells and adipose endothelial cells from inflamed visceral adipose tissue migrate to tumor sites.46

Stromal cells in the tumor microenvironment promote angiogenesis and support tumor progression.47Levels of inflammatory cytokines, such as IL-6 and TNF-α seem to be associated with more advanced tumors and hence poor prognosis,48 perhaps reflecting the known association between cancer cachexia and increased inflammation.49

However, there appears to be increased serum IL-6 in patients with a colorectal adenoma.50,51 Whether IL-6 is a biomarker of inflammation or plays a causal role in cancer development is an area for future study. Preclinical studies have shown promotion of progression of colon cancer cells by IL-6,52,53 and in animals of colon cancer, IL-6 seems to enhance colon tumor growth.54

A potential confounding factor in the role of inflammation in obesity and carcinogenesis is the find that systemic inflammation is increased in patients with a diet high in fat and refined sugar.55 Adherence to a Mediterranean diet (rich in vegetables, fruit, legumes, and grains) attenuates inflammation in healthy adults.56

Studies in mice have indicated that this inflammation is mediated by changes in the gut microbiota,57 and it may be that obesity is merely a marker of this metabolic dysregulation rather than a key driver in systemic inflammation.

Diet-induced weight loss decreases systemic inflammation in a randomized controlled trial of obese patients, even if the amount of weight loss (on average 5.6%) was not enough to reverse the obese state.58