Introduction
The current obesity juggernaught affecting the developed world appears unstoppable and has serious implications on the health of the population. The consequences to cardiovascular disease are well appreciated, but the potential links with cancers of the gastrointestinal (GI) tract are less well known. This short review documents the biological mechanisms on how obesity may lead to cancer, the supportive epidemiological data and the potential impact the increased number of cancers will have on general practitioners, hospital doctors and public health physicians.
Biological mechanisms for the effects of obesity
There are several plausible biological mechanisms for how obesity may promote carcinogenesis including: hyperinsulinaemia, hormonal changes, increased inflammation and local physical factors. These may influence several pathophysiological processes including tumour initiation and progression. One of the more developed hypotheses suggests that increased insulin and insulin-like growth factor 1 (IGF-1) levels in overweight and obese individuals promote carcinogenesis.1 Chronic hyperinsulinaemia is common in obese subjects and bioavailable IGF-1 is also elevated. IGF-1 is a potent mitogen and prevents cell death (anti-apoptotic effect) leading to increased cellular proliferation and differentiation by stimulating DNA synthesis.2 Furthermore, both insulin and IGF-1 down regulate sex hormone binding globulin (SHBG) resulting in an increase in serum oestrogens and androgens. Sex hormones are mitogens that may contribute to GI proliferation. Adipose tissue also up regulates inflammatory mediators including cytokines, such as TNF-alpha and interleukin-6 (IL-6). Adipose tissue, particularly visceral tissue, is a source of cytokines with serum leptin and IL-6 correlating well with increasing body mass index. While many GI cancers are associated with pre-malignant inflammatory states it is not yet understood how adipose-derived cytokines may influence this process. Of relevance is that TNF-alpha and IL-6 are potent mitogens. Finally, local physical factors may be important; oesophageal reflux increases with increased abdominal adiposity. The refluxate can promote Barrett's metaplasia and consequently adenocarcinoma.
Epidemiological evidence
The experimental work is supported by data from multiple epidemiological studies reporting positive associations between obesity and cancers of the oesophagus, pancreas and large bowel. For colorectal cancer, the most common cancer of the digestive tract, a meta-analysis of 31 epidemiological studies assessed the effects of obesity in 70,000 incident cases.3 The estimated relative risk of colorectal cancer was 1.19 (95% confidence interval (CI) = 1.11 to 1.29) in obese people (BMI >30 kg/m2) compared to those with a normal weight (BMI <25 kg/m2). A dose-response existed with every 2 kg/m2 increase in BMI (approximately 5 kg of extra weight) increasing the risk by 7% (95% CI = 4 to 10). If the association is causal, then a 2kg/m2 reduction in BMI in the population would prevent approximately 2,600 colorectal cancers annually in the UK.4 In pancreatic cancer, a tumour with an extremely poor prognosis, the effect of obesity was studied in a meta-analysis of 6,391 cases.5 The summary relative risk per unit increase in BMI was 1.02 (95% CI = 1.01 to 1.03), as in a 2% increase risk for each unit of BMI. This translates for those with a BMI of over 30 kg/m2 into a relative risk of 1.19 (95% CI = 1.10 to 1.29) compared to those with a BMI of 22 kg/m2. A reduction of two units in the population's BMI would reduce the annual number of cases of pancreatic cancer in the UK by 300. For oesophageal adenocarcinoma, whose incidence has risen faster than any other cancer of the digestive tract, a meta-analysis of six case-control studies reported a 54% (95% CI = 39% to 71%) increased risk with each 5 kg/m2 rise in BMI.6 Based on these figures, a relatively large reduction in BMI of one standard category (5 kg/m2) could prevent approximately 3,100 cases of oesophageal adenocarcinoma in the UK.
Conclusions
While the link between obesity and cardiovascular disease is well established there is now emerging evidence supporting a causal association with cancers of the GI tract. A more detailed understanding of the biological mechanisms is still needed to confirm the link, but the potential rise in these cancers should prompt action to encourage a reduction in the BMI of the population. A decrease in the BMI by two units may prevent approximately 4,000 cases of digestive cancers annually in the UK. This strategy would be of relevance to general practitioners and public health physicians to help prevent cancer, to medical and surgical gastroenterologists and oncologists to reduce the number of patients referred with cancer, and to managers who would need to deal with the increased resources required. Perhaps in this century, obesity will be identified as the main risk factor for cancers of the digestive tract, just as in the last, smoking was for lung cancer.
Footnotes
Letters not directly related to articles published in Clinical Medicine and presenting unpublished original data should be submitted for publication in this section. Clinical and scientific letters should not exceed 500 words and may include one table and up to five references.
- Royal College of Physicians
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