Obesity, inflammation and iron metabolism in colorectal carcinogenesis

  • Topic: Colorectal Cancer
  • Institution: University of Birmingham
  • Country: United Kingdom
  • Status: Completed

Scientific abstract

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Background

Whilst raised Body Mass Index (BMI) and leptin levels are associated with colorectal adenoma and carcinoma development, the exact cellular/molecular role of these factors in human colorectal carcinogenesis remains unidentified.

We hypothesised that raised leptin levels (associated with obesity) trigger interleukin-6 and the master regulator of iron metabolism, hepcidin, which in concert are prerequisite for human adenoma/colorectal cancer development. To date whilst leptin has been shown to be associated with raised IL-6 and hepcidin this has been described only in in-vitro hepatocellular models.

Methods

Serum collected from 200 people who had undergone colonoscopic screening as part of the National Bowel Cancer Screening Programme were utilised for this study. Importantly, detailed socio-demographic, symptoms and outcomes data were available for all participants. The levels of adipokines including leptin, IL-6 and hepcidin were determined in all samples and the interrelationship of these factors with serum iron indices, BMI and adenoma/cancer prevalence was investigated.

Results

When considering all patient groups (with or without neoplasia) there was a positive correlation between BMI and IL6 and BMI and leptin (P<0.01) as expected. Whilst serum hepcidin levels did not correlate with BMI, leptin or IL6 levels there was a strong association with haemoglobin (p=0.002) and transferrin concentration (p=0.004) indicating that body iron stores influence hepcidin expression.

The individuals who had progressed to carcinoma had significantly lower BMI than normals (p<0.01) and also had higher levels of IL6 (p<0.01), and, although not anaemic by WHO criteria had lower haemoglobin than normals (p<0.05). Comparing data from patients with high risk polyps and cancers together against normal individuals, although hepcidin, ferritin and transferrin levels did not differ, there was a positive correlation between serum hepcidin and ferritin (p<0.05) and a negative correlation between serum hepcidin and transferrin (p<0.01). Interestingly, in this small group of patients there was also a trend for hepcidin to correlate with serum IL6 and a highly significant correlation between hepcidin and leptin.

Conclusions

In summary across the whole cohort the known relationships between BMI, IL6 and leptin exist. Similarly hepcidin levels correlated with body iron stores as previously described. However, in patients with neoplasia serum hepcidin levels appeared to be predominantly correlated with the inflammatory markers IL-6, leptin and ferritin. In the context of our previous published findings this might suggest that inhibiting IL-6 and or leptin may provide a platform for inhibiting hepcidin expression and colorectal tumourigenesis.

Plain language abstract

Hypothesis

Raised circulating leptin levels which are associated with obesity trigger the hormone hepcidin, which is largely responsible for regulating body iron metabolism. However, we hypothesise that raised hepcidin and leptin levels are crucial to the development of bowel cancer. Thus decreasing BMI and thus leptin levels, through exercise may provide a platform for preventing hepcidin expression and bowel carcinogenesis.

Background

While raised Body Mass Index (BMI) and leptin levels are associated with bowel cancer development, the exact cellular/molecular role of these factors in human bowel carcinogenesis remains unidentified. In addition we have previously shown that hepcidin; the major hormone which regulates body iron levels, is also elevated in the blood of patients with advanced bowel cancer and this previously described liver hormone is also highly expressed in bowel cancer tissue. Further evidence suggests that hepcidin is likely to be fundamental to the process of bowel cancer. Hepcidin however, can be regulated by multiple factors including body iron stores and cytokines such as IL-6, in addition to leptin. However, the ability of leptin to regulate hepcidin has only ever been observed in artificial liver cell culture experiments. What is regulating hepcidin in human colorectal tumourigenesis remains unclear. Thus the aims of this study were to determine the levels of the various regulators of hepcidin and hepcidin itself in patients with or without varying grades of bowel cancer.

Methods

Serum collected from 200 people who had undergone colonoscopic screening as part of the National Bowel Cancer Screening Programme were utilised for this study. The levels of hepcidin and known regulators of hepcidin (leptin, IL-6 and body iron stores) were determined in all samples and the interrelationship of these factors with serum iron indices, BMI and adenoma/cancer prevalence was investigated.

Key findings

In healthy disease free individuals and patients with low burden colorectal disease hepcidin levels were associated with markers of body iron stores but not markers of inflammation and obesity. However, in patients with colorectal disease hepcidin levels were no longer associated with body iron stores but were now regulated by leptin. Thus we predict that it is obesity and the subsequent increase in leptin which triggers hepcidin expression in this high risk group and this exacerbates the risk of developing advanced bowel cancer. By decreasing body weight either through better dietary management, bariatric surgery and or exercise this could diminish leptin levels and in turn hepcidin levels which is likely to be a crucial trigger for bowel cancer development.