小柯机器人

美国威尔康奈尔医学院David Lyden等研究人员合作发现，肿瘤细胞外囊泡和颗粒诱发肝脏代谢功能紊乱。2023年5月24日，《自然》杂志在线发表了这项成果。

研究人员表明，炎症、脂肪肝和代谢紊乱是小鼠模型和肝外转移患者的系统性肝脏的特征。研究人员发现肿瘤衍生的细胞外囊泡和颗粒（EVP）是癌症诱导的肝脏重编程的关键媒介，可以通过耗尽Rab27a减少肿瘤EVP的分泌来扭转这一趋势。所有的EVP亚群，外泌体和主要是外泌颗粒，都能使肝功能失调。肿瘤EVP的脂肪酸货物（特别是棕榈酸）诱导库普弗细胞分泌肿瘤坏死因子（TNF），产生一个促炎症的微环境，抑制脂肪酸代谢和氧化磷酸化，并促进脂肪肝形成。值得注意的是，库普弗细胞去除或TNF阻断明显减少了肿瘤诱导的脂肪肝生成。肿瘤植入或用肿瘤EVP预处理会减少细胞色素P450基因的表达，并以TNF依赖的方式减弱药物代谢。研究人员还在后来发生肝外转移的胰腺癌患者的无瘤肝脏中观察到诊断时的脂肪肝和细胞色素P450表达的降低，突出了这项发现的临床意义。

值得注意的是，肿瘤EVP改造增强了化疗的副作用，包括骨髓抑制和心脏毒性，表明肿瘤源性EVP对肝脏的代谢重编程可能限制了癌症患者的化疗耐受性。这些研究结果揭示了肿瘤源性EVP如何失调肝脏功能，以及它们与TNF抑制一起防止脂肪肝形成和提高化疗疗效的可靶向潜力。

据悉，癌症改变了转移目标以外的多个器官的功能。

附：英文原文

Title: Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Author: Wang, Gang, Li, Jianlong, Bojmar, Linda, Chen, Haiyan, Li, Zhong, Tobias, Gabriel C., Hu, Mengying, Homan, Edwin A., Lucotti, Serena, Zhao, Fengbo, Posada, Valentina, Oxley, Peter R., Cioffi, Michele, Kim, Han Sang, Wang, Huajuan, Lauritzen, Pernille, Boudreau, Nancy, Shi, Zhanjun, Burd, Christin E., Zippin, Jonathan H., Lo, James C., Pitt, Geoffrey S., Hernandez, Jonathan, Zambirinis, Constantinos P., Hollingsworth, Michael A., Grandgenett, Paul M., Jain, Maneesh, Batra, Surinder K., DiMaio, Dominick J., Grem, Jean L., Klute, Kelsey A., Trippett, Tanya M., Egeblad, Mikala, Paul, Doru, Bromberg, Jacqueline, Kelsen, David, Rajasekhar, Vinagolu K., Healey, John H., Matei, Irina R., Jarnagin, William R., Schwartz, Robert E., Zhang, Haiying, Lyden, David

Issue&Volume: 2023-05-24

Abstract: Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs—particularly palmitic acid—induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

DOI: 10.1038/s41586-023-06114-4

Source: https://www.nature.com/articles/s41586-023-06114-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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