Editors' ChoiceCancer

Exosomes prep the metastatic site

Sci. Signal.  09 Jun 2015:
Vol. 8, Issue 380, pp. ec150
DOI: 10.1126/scisignal.aac7366

Extracellular vesicles called exosomes are emerging as an important mediator of cell-cell communication in various disease contexts, including the progression of cancer (see Zhang and Wang). Costa-Silva et al. found that exosomes secreted by pancreatic ductal adenocarcinoma (PDAC) cells carry a protein that primes the liver for metastatic colonization. In wild-type mice, a greater number of murine PDAC cells expressing mCherry, which were injected into the spleen, colonized the liver in mice that had previously received injections of PDAC-derived exosomes into the eye than in mice that had received injections of normal pancreatic tissue-derived exosomes. Tagging the exosomes with a fluorescent marker revealed that specialized, liver-resident macrophages called Kupffer cells specifically took up the PDAC-derived exosomes, but that neither Kupffer cells nor cells in any other tissue analyzed took up the exosomes from normal pancreatic tissue. Injecting mice with PDAC-derived exosomes increased the recruitment of innate immune cells, including macrophages and neutrophils, and altered the composition of the extracellular matrix in the liver as a result of increased production of fibronectin by hepatic stellate cells. In cultured human Kupffer cells, mRNA analysis revealed that coculture with PDAC-derived exosomes increased the expression of genes associated with liver fibrosis; among these, the gene encoding transforming growth factor–β (TGF-β) was the most highly expressed. Injecting mice with a TGF-β inhibitor reduced the amount of macrophage recruitment and fibronectin induction after splenic injection with PDAC-derived exosomes. Transiently depleting macrophages in the mice using diphtheria toxin prevented the increase in PDAC cell colonization caused by exosome injection. Mining mass spectrometry data from pancreatic exosomes identified macrophage migration inhibitory factor (MIF) as a potential mediator. Knocking down MIF in PDAC cells did not affect the size or binding of released exosomes to Kupffer cells but decreased the abundance of TGF-β and fibronectin in the liver and reduced the number of PDAC cells that colonized the liver in mice pre-injected with the exosomes. The findings suggest that PDAC exosomes create a prometastatic environment in the liver.

B. Costa-Silva, N. M. Aiello, A. J. Ocean, S. Singh, H. Zhang, B. K. Thakur, A. Becker, A. Hoshino, M. T. Mark, H. Molina, J. Xiang, T. Zhang, T.-M. Theilen, G. García-Santos, C. Williams, Y. Ararso, Y. Huang, G. Rodrigues, T.-L. Shen, K. J. Labori, I. M. B. Lothe, E. H. Kure, J. Hernandez, A. Doussot, S. H. Ebbesen, P. M. Grandgenett, M. A. Hollingsworth, M. Jain, K. Mallya, S. K. Batra, W. R. Jarnagin, R. E. Schwartz, I. Matei, H. Peinado, B. Z. Stanger, J. Bromberg, D. Lyden, Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015). [PubMed]

Y. Zhang, X.-F. Wang, A niche role for cancer exosomes in metastasis. Nat. Cell Biol. 17, 709–711 (2015). [PubMed]