When recruited to a primary tumor, bone marrow–derived cells (BMDCs) promote the growth of the primary tumor and are conditioned by the primary tumor to colonize future metastatic sites. Peinado et al. investigated the role of exosomes, vesicles that are released extracellularly and that can transfer proteins between cells, in the communication between primary tumors and BMDCs. Several proteins were enriched in exosomes from individuals with stage 4 melanoma, including tyrosinase-related protein 2 (TRYP2), and increased abundance of TRYP2 in individuals with stage 3 melanoma correlated with the development of metastases. Individuals with stage 4 melanoma with protein-rich exosomes in their plasma had a lower survival rate than those with protein-poor exosomes, and exosomes from highly metastatic cell lines (such as B16-F10 cells) had higher protein concentrations than those from poorly metastatic cell lines (such as B16-F1 cells). In mice implanted with B16-F10 cells to create a primary tumor, the metastatic burden in lungs and bones was increased by intravenous injection of exosomes from B16-F10 cells compared with those from poorly metastatic B16-F1 cells. Irradiated mice reconstituted with bone marrow from mice injected with B16-F10–derived exosomes showed greater primary tumor growth and increased size and number of metastases compared with mice reconstituted with bone marrow from control mice. Proteomic profiling indicated that the receptor MET, which has been implicated in metastasis, was enriched in B16-F10–derived exosomes compared with those from B16-F1 cells, and total abundance and phosphorylation (and thus activation) of MET were increased in BMDCs from mice injected with B16-10–derived exosomes. Patients with stage 3 or 4 melanoma showed increased total abundance and phosphorylation of MET. Knocking down MET by RNAi in B16-F10 cells before exosome collection and injection attenuated formation of metastases in lungs and bones. RNAi-mediated knockdown of the small GTPase Rab27a (which is involved in vesicle trafficking) in B16-F10 cells reduced exosome secretion, and injection of exosomes into mice derived from these cells resulted in decreased primary tumor growth and lung metastasis. In the associated commentary, Somasundaram and Herlyn suggest that the presence of TRYP2 and MET in exosomes could be used to predict which melanoma patients are likely to develop metastases.
H. Peinado, M. Alečković, S. Lavotshkin, I. Matei, B. Costa-Silva, G. Moreno-Bueno, M. Hergueta-Redondo, C. Williams, G. García-Santos, C. M. Ghajar, A. Nitadori-Hoshino, C. Hoffman, K. Badal, B. A. Garcia, M. K. Callahan, J. Yuan, V. R. Martins, J. Skog, R. N. Kaplan, M. S. Brady, J. D. Wolchok, P. B. Chapman, Y. Kang, J. Bromberg, D. Lyden, Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012). [Online Journal]
R. Somasundaram, M. Herlyn, Melanoma exosomes: Messengers of metastasis. Nat. Med. 18, 853–854 (2012). [Online Journal]