The advanced glycation endproduct Nε-carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention

Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, Western diet and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation endproducts (AGEs), which characterizes all the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumor-promoting role of RAGE, the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE Nε-carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumor growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration- and time-dependent manner, and activated downstream tumorigenic signaling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in 8/11 (72.7%) CML-treated versus 1/11 (9.1%) vehicle-treated (Ctr) mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, likely due to competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homolog CD166/ALCAM, which also favored tumor spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for risk management and prevention of PaC