Advanced Glycation End Products, Soluble Receptor for Advanced Glycation End Products, and Risk of Colorectal Cancer

Abstract

Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement. We examined the association between N(ε)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI. Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26). Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers. This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development.