TANG-LONG SHEN2018-09-102018-09-102015-06http://europepmc.org/abstract/med/25985394http://scholars.lib.ntu.edu.tw/handle/123456789/392548Pancreatic 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. ? 2015 Macmillan Publishers Limited. All rights reserved.[SDGs]SDG1[SDGs]SDG3alpha smooth muscle actin; collagen type 1; connective tissue growth factor; fibronectin; macrophage migration inhibition factor; platelet derived growth factor; tenascin; transforming growth factor beta; vitronectin; fibronectin; macrophage migration inhibition factor; small interfering RNA; transforming growth factor beta; animal cell; animal experiment; animal model; animal tissue; Article; bone marrow derived macrophage; cancer prognosis; cancer staging; cell activation; cell communication; cell differentiation; cell function; cell infiltration; cell migration; cell population; cell transport; controlled study; CTGF gene; down regulation; EDN gene; exosome; fibrogenesis; gene; gene expression regulation; human; IGF gene; Kupffer cell; liver metastasis; mouse; myofibroblast; nonhuman; pancreas adenocarcinoma; pancreas cancer; PDGF gene; priority journal; protein expression; protein function; protein secretion; protein synthesis; TGF beta gene; tumor volume; upregulation; animal; biosynthesis; bone marrow cell; C57BL mouse; cell motion; cytology; exosome; female; genetics; hepatic stellate cell; immunology; knockout mouse; liver; liver tumor; macrophage; metabolism; nucleotide sequence; pancreas carcinoma; pancreas tumor; pathology; precancer; RNA interference; secondary; secretion (process); sequence analysis; signal transduction; tumor cell line; Mus; Animals; Base Sequence; Bone Marrow Cells; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Exosomes; Female; Fibronectins; Gene Expression Regulation, Neoplastic; Hepatic Stellate Cells; Humans; Liver; Liver Neoplasms; Macrophage Migration-Inhibitory Factors; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatic Neoplasms; Precancerous Conditions; RNA Interference; RNA, Small Interfering; Sequence Analysis, RNA; Signal Transduction; Transforming Growth Factor betajournal article10.1038/ncb3169