期刊
NATURE MEDICINE
卷 18, 期 6, 页码 883-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2753
关键词
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资金
- Children's Cancer and Blood Foundation
- Manning Foundation
- Hartwell Foundation
- Pediatric Oncology Experimental Therapeutics Investigators Consortium
- Stavros S. Niarchos Foundation
- Champalimaud Foundation
- Nancy C. and Daniel P. Paduano Foundation
- Mary Kay Foundation
- American Hellenic Educational Progressive Association
- Malcolm Hewitt Wiener Foundation
- George Best Costacos Foundation
- NCI [NCI-R01CA 098234-01]
- National Foundation for Cancer Research
- Susan G. Komen for the Cure
- Fundacion para el Fomento en Asturias de la Investigacion Cientifica Aplicada y la Tecnologia
- Fundacion Universidad de Oviedo
- Beth C. Tortolani Foundation
- Sussman Family Fund
- Charles and Marjorie Holloway Foundation
- Manhassat Breast Cancer Fund
- NIH [CA87637, R01-CA134519, R01-CA141062]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
- National Science Foundation [CBET-0941143]
- American Society
- [NCI-U54-CA143836]
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.
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