| Literature DB >> 25985394 |
Bruno Costa-Silva1, Nicole M Aiello2, Allyson J Ocean3, Swarnima Singh1, Haiying Zhang1, Basant Kumar Thakur4, Annette Becker1, Ayuko Hoshino1, Milica Tešić Mark5, Henrik Molina5, Jenny Xiang6, Tuo Zhang6, Till-Martin Theilen1, Guillermo García-Santos1, Caitlin Williams1, Yonathan Ararso1, Yujie Huang1, Gonçalo Rodrigues7, Tang-Long Shen8, Knut Jørgen Labori9, Inger Marie Bowitz Lothe10, Elin H Kure11, Jonathan Hernandez12, Alexandre Doussot12, Saya H Ebbesen1, Paul M Grandgenett13, Michael A Hollingsworth13, Maneesh Jain14, Kavita Mallya14, Surinder K Batra14, William R Jarnagin12, Robert E Schwartz15, Irina Matei1, Héctor Peinado16, Ben Z Stanger2, Jacqueline Bromberg17, David Lyden18.
Abstract
Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.Entities:
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Year: 2015 PMID： 25985394 PMCID： PMC5769922 DOI： 10.1038/ncb3169
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824