Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
Date Issued
2015-06
Author(s)
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. ? 2015 Macmillan Publishers Limited. All rights reserved.
Other Subjects
alpha 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 beta
Type
journal article