Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue.
Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue.
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DOI：
10.1136/gutjnl-2014-308350
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发表时间：
2016-07
期刊：
影响因子：
24.5
通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
--
作者：
Sagar G;Sah RP;Javeed N;Dutta SK;Smyrk TC;Lau JS;Giorgadze N;Tchkonia T;Kirkland JL;Chari ST;Mukhopadhyay D
在临床表现为胰腺癌（PC）前几个月出现的新发糖尿病和伴随的体重减轻似乎是由肿瘤分泌产物引起的副肿瘤现象。我们最近的研究结果表明外泌体肾上腺髓质素（AM）在PC患者糖尿病的发展中起重要作用。脂肪组织脂解可能是PC患者早发性体重减轻的原因。我们假设，脂溶酶诱导的货物是由PC脱落的外泌体携带的，并负责副肿瘤效应。因此，在本研究中，我们研究了PC分泌的外泌体是否会诱导脂肪细胞的脂肪分解，并探讨了AM在PC外泌体中作为这种脂肪分解的介质的作用。从患者来源的细胞系以及PC患者和非PC对照的血浆中分离并鉴定了外泌体。将分化的小鼠（3T3-L1）和人脂肪细胞暴露于这些外泌体中以研究脂肪分解。甘油实验和免疫印迹法研究脂肪分解。采用多联法研究外泌体处理脂肪细胞时AM与AM受体（ADMR）的相互作用。在小鼠和人类脂肪细胞中，我们发现AM和pc -外泌体都能促进脂肪分解，而AM受体阻断则能消除这一作用。AM与其在脂肪细胞上的受体相互作用，激活p38和ERK1/2 MAPKs，并通过磷酸化激素敏感脂肪酶促进脂肪分解。PKH67标记的pc -外泌体很容易内化到脂肪细胞中，并参与了小窝蛋白和巨噬细胞作用，作为内吞作用的可能机制。胰腺癌分泌外泌体诱导皮下脂肪组织脂解；外泌体肾上腺髓质素是这种作用的候选介质。
New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumor-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesize that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC exosomes as the mediator of this lipolysis. Exosomes from patient derived cell lines and from plasma of PC patients and non-PC controls were isolated and characterized. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink assay was used to study AM and AM receptor (ADMR) interaction in adipocytes treated with exosomes. In murine and human adipocytes we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by AM receptor blockade. AM interacted with its receptor on the adipocytes, activated p38 and ERK1/2 MAPKs and promoted lipolysis by phosphorylating hormone sensitive lipase. PKH67 labeled PC-exosomes were readily internalized into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. Pancreatic cancer secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal adrenomedullin is a candidate mediator of this effect.