Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver Journal Article
| Authors: | Costa-Silva, B.; Aiello, N. M.; Ocean, A. J.; Singh, S.; Zhang, H.; Thakur, B. K.; Becker, A.; Hoshino, A.; Mark, M. T.; Molina, H.; Xiang, J.; Zhang, T.; Theilen, T. M.; García-Santos, G.; Williams, C.; Ararso, Y.; Huang, Y.; Rodrigues, G.; Shen, T. L.; Labori, K. Jø; Lothe, I. M. B.; Kure, E. H.; Hernandez, J.; Doussot, A.; Ebbesen, S. H.; Grandgenett, P. M.; Hollingsworth, M. A.; Jain, M.; Mallya, K.; Batra, S. K.; Jarnagin, W. R.; Schwartz, R. E.; Matei, I.; Peinado, H.; Stanger, B. Z.; Bromberg, J.; Lyden, D. |
| Article Title: | Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver |
| 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. |
| Keywords: | platelet derived growth factor; controlled study; protein expression; nonhuman; pancreas cancer; cancer staging; protein function; animal cell; mouse; animal tissue; gene; mus; cell function; cell infiltration; tumor volume; transforming growth factor beta; animal experiment; animal model; cell differentiation; cell population; alpha smooth muscle actin; collagen type 1; gene expression regulation; liver metastasis; protein synthesis; cell migration; protein secretion; pancreas adenocarcinoma; kupffer cell; down regulation; upregulation; myofibroblast; cell transport; cell activation; cell communication; connective tissue growth factor; vitronectin; fibronectin; exosome; macrophage migration inhibition factor; tenascin; cancer prognosis; pdgf gene; human; priority journal; article; bone marrow derived macrophage; ctgf gene; edn gene; fibrogenesis; igf gene; tgf beta gene |
| Journal Title: | Nature Cell Biology |
| Volume: | 17 |
| Issue: | 6 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-06-01 |
| Start Page: | 816 |
| End Page: | 826 |
| Language: | English |
| DOI: | 10.1038/ncb3169 |
| PROVIDER: | scopus |
| PUBMED: | 25985394 |
| PMCID: | PMC5769922 |
| DOI/URL: | |
| Notes: | Export Date: 2 July 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work