Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression.

Publication Type:

Journal Article

Source:

Blood, Volume 115, Issue 9, p.1755-64 (2010)

Keywords:

beta Catenindigestive disease, digestive deseases Bone Marrow Cellsdigestive disease, digestive deseases Cell Linedigestive disease, digestive deseases Cell-Derived Microparticlesdigestive disease, digestive deseases Disease Progressiondigestive disease, digestive deseases Glycogen Synthase Kinase 3digestive disease, digestive deseases Humansdigestive disease, digestive deseases Hypoxia-Inducible Factor 1, alpha Subunitdigestive disease, digestive deseases Intracellular Signaling Peptides and Proteinsdigestive disease, digestive deseases Leukemia, Lymphocytic, Chronic, B-Celldigestive disease, digestive deseases Microscopy, Electron, Transmissiondigestive disease, digestive deseases Protein-Serine-Threonine Kinasesdigestive disease, digestive deseases Proto-Oncogene Proteins c-aktdigestive disease, digestive deseases Ribosomal Protein S6 Kinases, 70-kDadigestive disease, digestive deseases Signal Transductiondigestive disease, digestive deseases Stromal Cellsdigestive disease, digestive deseases TOR Serine-Threonine Kinasesdigestive disease, digestive deseases Tumor Cells, Cultureddigestive disease, digestive deseases Vascular Endothelial Growth Factor A

Abstract:

Microvesicles (MVs) released by malignant cancer cells constitute an important part of the tumor microenvironment. They can transfer various messages to target cells and may be critical to disease progression. Here, we demonstrate that MVs circulating in plasma of B-cell chronic lymphocytic leukemia (CLL) patients exhibit a phenotypic shift from predominantly platelet derived in early stage to leukemic B-cell derived at advanced stage. Furthermore, the total MV level in CLL was significantly greater compared with healthy subjects. To understand the functional implication, we examined whether MVs can interact and modulate CLL bone marrow stromal cells (BMSCs) known to provide a "homing and nurturing" environment for CLL B cells. We found that CLL-MV can activate the AKT/mammalian target of rapamycin/p70S6K/hypoxia-inducible factor-1alpha axis in CLL-BMSCs with production of vascular endothelial growth factor, a survival factor for CLL B cells. Moreover, MV-mediated AKT activation led to modulation of the beta-catenin pathway and increased expression of cyclin D1 and c-myc in BMSCs. We found MV delivered phospho-receptor tyrosine kinase Axl directly to the BMSCs in association with AKT activation. This study demonstrates the existence of separate MV phenotypes during leukemic disease progression and underscores the important role of MVs in activation of the tumor microenvironment.