The advanced glycation end-product Nε-carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention
The advanced glycation end-product Nε-carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention
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DOI：
10.1002/path.5072
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发表时间：
2018-06-01
影响因子：
7.3
通讯作者：
Pugliese, Giuseppe
中科院分区：
文献类型：
--
作者：
Menini, Stefano;Iacobini, Carla;Pugliese, Giuseppe
糖尿病是胰腺癌（PaC）的一个确定的危险因素，与肥胖、西方饮食和吸烟一起。共同的机制联系可能是晚期糖基化终产物（AGEs）的积累，这是上述所有疾病状况和不健康习惯的特征。然而，令人惊讶的是，尽管有证据表明晚期糖基化终产物受体（RAGE） （AGEs的受体）具有促肿瘤作用，但AGEs在PaC中的作用尚未得到研究。在这里，我们验证了age通过RAGE激活促进PaC的假设。为此，我们研究了AGE N-epsilon-carboxymethyllysine （CML）在人胰腺导管腺癌（PDA）细胞系和kras驱动PaC与生物发光增殖模型杂交的小鼠模型中的作用。在体内用生物发光显像监测肿瘤的生长，并用组织学证实肿瘤的生长。CML以浓度依赖性和时间依赖性的方式促进PDA细胞生长和RAGE表达，并激活下游肿瘤信号通路。这些作用被RAGE拮抗剂肽（RAP）所抵消。给PaC易感性小鼠外源性AGE诱导胰腺上皮内肿瘤（PanINs）的RAGE上调，并显著加速向侵袭性PaC的进展。在11周龄（CML治疗6周）时，11只CML治疗小鼠中有8只（72.7%）出现PaC，而11只对照（Ctr）小鼠中有1只（9.1%）出现PaC。RAP在Ctr小鼠中延迟了PanIN的发展，但在cml处理小鼠中未能阻止PaC的促进，可能是因为与可溶性RAGE结合age和/或RAGE同源CD166/活化的白细胞粘附分子的代偿性上调，这也有利于肿瘤的扩散。这些发现表明，AGEs通过受体介导的机制调节PaC的发生和进展，并且可能是糖尿病和其他以AGE积累增加为特征的疾病所带来的额外风险的原因。最后，我们的数据表明，降低AGE的策略，而不是抑制RAGE，可能更适合PaC的风险管理和预防。Copyright (C) 2018大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
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-epsilon-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 (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.