Colorectal cancer is one of the most common cancer in the United States. Several environmental and lifestyle risk factors have been identified for colorectal cancer and adenomas; however, their mechanism of action in colon carcinogenesis remains largely unanswered. Given a wealth of data on the inverse association between non-steroidal anti-inflammatory drugs (NSAIDs) and colorectal neoplasia, inflammation is a plausible pathway to be studied. In addition, a growing literature has redefined obesity, which has been positively associated with colorectal neoplasia, as a state of low grade systemic inflammation. The goal of this dissertation was to explore the associations between obesity, inflammation and colorectal neoplasia using data from three studies.
We examined circulating levels of CRP, IL-6, and TNF-α in relation to risk factors and the prevalence of colorectal adenomas in 873 participants from a colonoscopy-based cross-sectional study. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines such as older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-α, and to a lesser degree, with CRP. For IL-6, adjusted odds ratios for colorectal adenomas were 1.69 (95% confidence interval [CI]: 1.13-2.54) for the second highest plasma level, and 1.80 (95% CI: 1.22-2.66) for the highest level compared with the reference level. A similar association was found with TNF-α, with adjusted odds ratios of 1.51 (95% CI: 1.01-2.27) and 1.59 (95% CI: 1.06-2.40), respectively. Our findings suggest that systemic inflammatory cytokines might be involved in the early development of colorectal neoplasia, and suggest that systemic inflammation might mediate the association with obesity and other risk factors.
We further investigated whether an inverse associations between NSAIDs and colorectal neoplasia was more pronounced in obese individuals, who presumably have increased levels of circulating inflammatory cytokines compared to non-obese individuals, using the two datasets from (1) a population-based case-control study of distal large bowel cancer (i.e., sigmoid, rectosigmoid and rectal cancer) among whites and African Americans in North Carolina, and (2) a completed randomized controlled trial of aspirin 325 mg daily to prevent colorectal adenomas in patients with a history of colorectal cancer.
In the case-control study of distal large bowel cancer, regular NSAID use was inversely associated with distal colorectal cancer in whites, but not in African Americans (for regular vs. non-regular use, whites: OR = 0.51, 95% CI: 0.39-0.66; African Americans: OR = 0.99, 95% CI: 0.60-1.63). Also, there was an elevated risk of incident colorectal adenomas in relation to high BMI in patients with prior colorectal cancer (BMI ≥ 30kg/m 2: OR = 1.42, 95% CI: 0.90-2.24). However, there is little evidence suggesting a more pronounced inverse association between NSAIDs/aspirin and colorectal neoplasia among obese versus non-obese individuals in either of the two studies.