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The advanced glycation end‐product Nϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention
Authors:Stefano Menini  Carla Iacobini  Luisa de Latouliere  Isabella Manni  Vittoria Ionta  Claudia Blasetti Fantauzzi  Carlo Pesce  Paola Cappello  Francesco Novelli  Giulia Piaggio  Giuseppe Pugliese
Affiliation:1. Department of Clinical and Molecular Medicine, ‘La Sapienza’ University, Rome, Italy;2. Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy;3. DINOGMI, University of Genoa Medical School, Genoa, Italy;4. Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
Abstract:Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end‐products (AGEs), which characterizes all of 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 tumour‐promoting role of receptor for advanced glycation end‐products (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 N?‐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. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration‐dependent and time‐dependent manner, and activated downstream tumourigenic signalling 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 eight of 11 (72.7%) CML‐treated versus one of 11 (9.1%) vehicle‐treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML‐treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour 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 the risk management and prevention of PaC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords:pancreatic cancer  Kras mutation  advanced glycation end‐products  RAGE  diabetes  bioluminescence imaging
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