Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET Journal Article

   

Authors:	Peinado, H.; Alečković, M.; Lavotshkin, S.; Matei, I.; Costa-Silva, B.; Moreno-Bueno, G.; Hergueta-Redondo, M.; Williams, C.; García-Santos, G.; Ghajar, C. M.; Nitadori-Hoshino, A.; Hoffman, C.; Badal, K.; Garcia, B. A.; Callahan, M. K.; Yuan, J.; Martins, V. R.; Skog, J.; Kaplan, R. N.; Brady, M. S.; Wolchok, J. D.; Chapman, P. B.; Kang, Y.; Bromberg, J.; Lyden, D.
Article Title:	Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
Abstract:	Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45-C-KIT low/+TIE2 + bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process. © 2012 Nature America, Inc. All rights reserved.
Keywords:	controlled study; protein expression; unclassified drug; oncoprotein; human cell; nonhuman; mouse; phenotype; animals; mice; animal tissue; gene; bone marrow cells; mus; stem cell factor; melanoma; gene expression; cell line; animal experiment; animal model; rna interference; angiogenesis; mice, inbred c57bl; nucleotide sequence; heat shock protein 90; stem cells; metastasis potential; heat shock protein 70; hematopoietic stem cell; tumor growth; angiopoietin receptor; cd45 antigen; scatter factor receptor; metastatic melanoma; proto-oncogene proteins c-met; exosome; exosomes; very late activation antigen 4; rab gtp-binding proteins; protein tyrp2; rab1a gene; rab27a gene; rab5b gene; rab7 gene
Journal Title:	Nature Medicine
Volume:	18
Issue:	6
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Date Published:	2012-05-27
Start Page:	883
End Page:	891
Language:	English
DOI:	10.1038/nm.2753
PROVIDER:	scopus
PUBMED:	22635005
PMCID:	PMC3645291
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84862007577&partnerID=40&md5=299945fa80838207746ee4623469631d
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 2 July 2012" - "CODEN: NAMEF" - "Source: Scopus"

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