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

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Autor(es):
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Peinado, Hector [1, 2, 3] ; Aleckovic, Masa [4] ; Lavotshkin, Simon [5] ; Matei, Irina [1, 2, 3] ; Costa-Silva, Bruno [1, 2, 3, 6] ; Moreno-Bueno, Gema [7, 8] ; Hergueta-Redondo, Marta [7, 8] ; Williams, Caitlin [1, 2, 3] ; Garcia-Santos, Guillermo [1, 2, 3] ; Ghajar, Cyrus M. [9] ; Nitadori-Hoshino, Ayuko [1, 2, 3] ; Hoffman, Caitlin [10] ; Badal, Karen [1, 2, 3] ; Garcia, Benjamin A. [4] ; Callahan, Margaret K. [11] ; Yuan, Jianda [12] ; Martins, Vilma R. [6] ; Skog, Johan [13] ; Kaplan, Rosandra N. [14] ; Brady, Mary S. [15] ; Wolchok, Jedd D. [11, 12] ; Chapman, Paul B. [11] ; Kang, Yibin [4, 16, 17] ; Bromberg, Jacqueline [11] ; Lyden, David [17, 1, 2, 3, 18]
Número total de Autores: 25
Afiliação do(s) autor(es):
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[1] Weill Cornell Med Coll, Dept Pediat, Childrens Canc & Blood Fdn Labs, New York, NY - USA
[2] Weill Cornell Med Coll, Dept Cell, Childrens Canc & Blood Fdn Labs, New York, NY - USA
[3] Weill Cornell Med Coll, Dept Dev Biol, Childrens Canc & Blood Fdn Labs, New York, NY - USA
[4] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 - USA
[5] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY - USA
[6] AC Camargo Hosp, Int Ctr Res & Educ, Sao Paulo - Brazil
[7] Univ Autonoma Madrid, Inst Invest Biomed Alberto Sols, IdiPAZ Inst Invest Sanitaria La Paz, CSIC, Dept Bioquim, Madrid - Spain
[8] Fdn MD Anderson Canc Ctr, Madrid - Spain
[9] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 - USA
[10] Weill Cornell Med Coll, Dept Neurosurg, New York, NY - USA
[11] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 - USA
[12] Sloan Kettering Inst, Ludwig Ctr Canc Immunotherapy, Dept Immunol, New York, NY - USA
[13] Exosome Diagnost Inc, New York, NY - USA
[14] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 - USA
[15] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 - USA
[16] Canc Inst New Jersey, Genom Instabil & Tumor Progress Program, New Brunswick, NJ - USA
[17] Champalimaud Metastasis Programme, Lisbon - Portugal
[18] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 - USA
Número total de Afiliações: 18
Tipo de documento: Artigo Científico
Fonte: Nature Medicine; v. 18, n. 6, p. 883+, JUN 2012.
Citações Web of Science: 1564
Resumo

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. (AU)