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Blood. 2015 Aug 27;126(9):1106-17. doi: 10.1182/blood-2014-12-618025. Epub 2015 Jun 22.

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.

Author information

1
Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
2
Department for Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
3
Luxembourg Clinical Proteomics Center, Luxembourg Institute of Health, Luxembourg, Luxembourg;
4
Integrated BioBank of Luxembourg, Luxembourg, Luxembourg;
5
INSERM U981, Gustave Roussy, Villejuif, France; Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France;
6
Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France; INSERM UMR1009, Gustave Roussy Villejuif, France; and.
7
Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.

Abstract

Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected α-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts.

PMID:
26100252
PMCID:
PMC4560344
DOI:
10.1182/blood-2014-12-618025
[Indexed for MEDLINE]
Free PMC Article

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