Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction.
Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction.
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DOI：
10.1158/1078-0432.ccr-14-2022
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发表时间：
2015-04-01
期刊：
影响因子：
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通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
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作者：
Javeed N;Sagar G;Dutta SK;Smyrk TC;Lau JS;Bhattacharya S;Truty M;Petersen GM;Kaufman RJ;Chari ST;Mukhopadhyay D
胰腺癌（PC）经常导致糖尿病。我们最近提出肾上腺髓质素（AM）作为PC胰腺β细胞功能障碍的候选介质。PC衍生的AM如何到达远离癌症的β细胞以诱导β细胞功能障碍尚不清楚。我们测试了一种新的假设，即PC将含有AM的外泌体释放到循环中，这些外泌体被转运到β细胞并损害胰岛素分泌。我们表征了来自PC细胞系的条件培养基（n=5）和PC患者的门静脉/外周静脉血（n=20）的外泌体。Western印迹分析显示PC-外泌体中存在AM。我们确定了含AM的PC-外泌体对INS-1 β细胞和人胰岛的胰岛素分泌的影响，并显示了外泌体如何内化到β细胞中。我们研究了β细胞AM受体与PC-外泌体中存在的AM之间的相互作用。此外，我们还研究了AM对β细胞内质网（ER）应激反应基因和活性氧/氮生成的影响。发现外泌体是PC分泌到培养基和人血浆中的主要细胞外囊泡。PC-外泌体含有AM和CA 19 -9，容易通过小窝蛋白介导的内吞或巨胞饮作用进入β细胞，并抑制胰岛素分泌。PC-外泌体中的AM与β细胞上的受体相互作用。AM受体阻断剂消除了外泌体对胰岛素分泌的抑制作用。暴露于AM或PC-外泌体的β-细胞显示ER应激基因的上调和活性氧/氮物质的增加。胰腺癌通过将AM+/CA 19 -9+外泌体脱落到抑制胰岛素分泌的循环中（可能通过AM诱导的ER应激和UPR失败）而引起副肿瘤性β细胞功能障碍。
Pancreatic cancer (PC) frequently causes diabetes. We recently proposed adrenomedullin (AM) as a candidate mediator of pancreatic β-cell dysfunction in PC. How PC-derived AM reaches β-cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that PC sheds AM-containing exosomes into circulation which are transported to β-cells and impair insulin secretion. We characterized exosomes from conditioned media of PC-cell lines (n=5) and portal/peripheral venous blood of PC patients (n=20). Western blot analysis showed the presence of AM in PC-Exosomes. We determined the effect of AM-containing PC-Exosomes on insulin secretion from INS-1 β-cells and human islets, and showed how exosomes internalize into β-cells. We studied the interaction between β-cell AM receptors and AM present in PC-Exosomes. In addition, we studied the effect of AM on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β-cells. Exosomes were found to be the predominant extracellular vesicles secreted by PC into culture media and human plasma. PC-Exosomes contained AM and CA19-9, readily entered β-cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. AM in PC-Exosomes interacted with its receptor on β-cells. AM receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β-cells exposed to AM or PC-Exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding AM+/CA19-9+ exosomes into circulation that inhibit insulin secretion, likely through AM-induced ER stress and failure of the UPR.