Circulating microvesicles in B cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression.
Circulating microvesicles in B cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression.
Blood. 2009 Dec 17;
Authors: Ghosh AK, Secreto CR, Knox TR, Ding W, Mukhopadhyay D, Kay NE
Microvesicles (MV) released by malignant cancer cells constitute an important part of the tumor-microenvironment as they can transfer various messages to target cells and may be critical to disease progression. Here, we demonstrate that MV circulating in plasma of B-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 higher compared to normal subjects. In an effort to understand the functional implication of the elevated MV level in CLL, we examined whether MV can interact and modulate CLL bone marrow stromal cells (BMSC) known to provide a "homing and nurturing" environment for CLL B-cells. We found that CLL-MV can activate the AKT/mTOR/p70S6K/HIF-1alpha axis in CLL-BMSC with production of VEGF, 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 BMSC. We found MV delivered phospho-receptor tyrosine kinase Axl directly to the BMSC in association with AKT activation. This study demonstrates the existence of separate MV phenotypes during leukemic disease progression, and underscores the important role of MV in activation of the tumor microenvironment.
PMID: 20018914 [PubMed - as supplied by publisher]
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