Editors' ChoiceCancer

Preparing for metastasis

Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ec347
DOI: 10.1126/scisignal.aad9146

Tumor cells from different cancers generally metastasize to specific organs; for example, breast cancer cells often target lungs and the bone, whereas pancreatic cancer cells mostly target the liver. Exosomes are small, extracellular vesicles that transport cellular contents over short or long distances from their cell of origin to a target cell. Hoshino et al. isolated exosomes from various human cancer cell lines, labeled them fluorescently, and injected them into nude mice. Imaging analysis showed that exosomes from cell lines known to target the lung were more enriched in the lungs than were exosomes from cell lines known to metastasize to the liver, and vice versa. When lung-tropic breast cancer cells (4175-LuT cells) were injected into mice that were preinjected with 4175-LuT–derived exosomes, the number of 4175-LuT cells that accumulated in the lungs was higher than that in mice injected with 4175-LuT cells alone. Furthermore, preinjection of mice with 4175-LuT exosomes increased the lung accumulation of 1833-BoT cells, which normally metastasize to the bone. Mass spectrometry and Western blotting analyses showed that the presence of distinct adhesion molecules called integrins in exosomes correlated with their organ specificity. Immunofluorescence analysis of mice injected with labeled exosomes revealed that lung-tropic exosomes were taken up by fibroblasts, liver-tropic exosomes were present in Kupffer cells, and brain-tropic exosomes accumulated in endothelial cells. Knocking down the integrin β4 subunit in 4175-LuT cells resulted in exosomes that exhibited decreased accumulation in the lungs of recipient mice; similar experiments showed that the integrin β5 subunit was required for efficient trafficking of exosomes to the liver. Repeated exposure of lung fibroblasts in culture to lung-tropic exosomes increased the expression of genes encoding proinflammatory factors that are associated with metastasis. Finally, exosomes isolated from the blood of patients with various cancers that had lung metastasis had increased amounts of the integrin β4 subunit compared with exosomes from cancer patients with liver metastasis or cancer patients with no detectable metastasis, suggesting that exosomes may act as biomarkers of metastatic sites. As Rak observes in commentary, how this increased understanding of organ-specific metastasis can be put to good use therapeutically will be the subject of future studies.

A. Hoshino, B. Costa-Silva, T.-L. Shen, G. Rodrigues, A. Hashimoto, M. T. Mark, H. Molina, S. Kohsaka, A. Di Giannatale, S. Ceder, S. Singh, C. Williams, N. Soplop, K. Uryu, L. Pharmer, T. King, L. Bojmar, A. E. Davies, Y. Ararso, T. Zhang, H. Zhang, J. Hernandez, J. M. Weiss, V. D. Dumont-Cole, K. Kramer, L. H. Wexler, A. Narendran, G. K. Schwartz, J. H. Healey, P. Sandstrom, K. J. Labori, E. H. Kure, P. M. Grandgenett, M. A. Hollingsworth, M. de Sousa, S. Kaur, M. Jain, K. Mallya, S. K. Batra, W. R. Jarnagin, M. S. Brady, O. Fodstad, V. Muller, K. Pantel, A. J. Minn, M. J. Bissell, B. A. Garcia, Y. Kang, V. K. Rajasekhar, C. M. Ghajar, I. Matei, H. Peinado, J. Bromberg, D. Lyden, Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015). [PubMed]

J. Rak, Organ-seeking vesicles. Nature 527, 312–314 (2015). [PubMed]

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