Evidence That Serum Levels of the Soluble Receptor for Advanced Glycation End Products Are Inversely Associated with Pancreatic Cancer Risk: A Prospective Study

Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of N-epsilon-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case-cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985-1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38-1.22), P-trend -0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23-0.73), P-trend = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers. Cancer Res; 71(10); 3582-9. (C) 2011 AACR.