Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a src-dependent fashion

Abstract

Exosomes, microvesicles of endocytic origin released by normal and tumor cells, play an important role in cell-to-cell communication. Angiogenesis has been shown to regulate progression of chronic myeloid leukemia (CML). The mechanism through which this happens has not been elucidated. We isolated and characterized exosomes from K562 CML cells and evaluated their effects on human umbilical endothelial cells (HUVECs). Fluorescent-labeled exosomes were internalized by HUVECs during tubular differentiation on Matrigel. Exosome localization was perinuclear early in differentiation, moving peripherally in cells undergoing elongation and connection. Exosomes move within and between nanotubular structures connecting the remodeling endothelial cells. They stimulated angiotube formation over a serum/growth factor-limited medium control, doubling total cumulative tube length (P = 0.003). Treatment of K562 cells with two clinically active tyrosine kinase inhibitors, imatinib and dasatinib, reduced their total exosome release (P <0.009); equivalent concentrations of drug-treated exosomes induced a similar extent of tubular differentiation. However, dasatinib treatment of HUVECs markedly inhibited HUVEC response to drug control CML exosomes (P <0.002). In an in vivo mouse Matrigel plug model angiogenesis was induced by K562 exosomes and abrogated by oral dasatinib treatment (P <0.01). K562 exosomes induced dasatinib-sensitive Src phosphorylation and activation of downstream Src pathway proteins in HUVECs. Imatinib was minimally active against exosome stimulation of HUVEC cell differentiation and signaling. Thus, CML cell-derived exosomes induce angiogenic activity in HUVEC cells. The inhibitory effect of dasatinib on exosome production and vascular differentiation and signaling reveals a key role for Src in both the leukemia and its microenvironment.

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

“…Furthermore, we showed that MM-MV-treated endothelial cells had enhanced levels of VEGF and IL-6, the key growth factors involved in myeloma [41] . These results support the role of MM-MVs in angiogenesis, consistent with findings in other cancers [12,14,21] . Of note, the origin of MMendothelial cells is actually unknown [42,43] .…”

“…Although these classical events have been commonly thought of as the predominant modes of cell-to-cell communication, a novel type of vesicle secretion has recently received a great deal of attention [8,9,15,33] . Though the secretion of exosomes by myeloma [21,34] , there have been no previous studies about MM-MVs. The current study identified MM-MVs as a potential mediator of angiogenesis.…”

“…In the present study, the biologically active molecules horizontally transferred to endothelial cells via MM-MVs may include more than sydecan-1 (CD138), and further studies are needed to explore their contents. Angiogenic cytokines, such as VEGF, have been discovered in exosomes from myeloma cells [21] . It is reasonable to believe that the enriched clusters of molecules in the MM-MVs, as a whole, may possess the ability to transform the target endothelial cells.…”

“…Recently, a growing body of evidence suggests that TMVs contain a selective enrichment of a discrete set of cellular molecules that can be transferred into the target cells [16][17][18][19] . Interestingly, Thompson et al [20] recently confirmed that exosomes, which are a different kind of vesicle with different origins, sizes and content, are secreted by myeloma cells, and emerging evidence has shown that TMVs act as novel angiogenic mediators and can stimulate angiogenesis in tumors [14,19,[21][22][23] ; however, it is not clear whether MVs can be secreted by myeloma cells (MM-MVs).…”

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

“…Using the KEGG pathways to analyze targets of dysregulated miRNAs across the progression of CML, we have found that many dysregulated potential target molecules were involved in several biological pathways including metabolic and cancer pathways, the MAPK signaling pathway, endocytosis, cytokine-cytokine receptor interaction and focal adhesion. Recent studies have confirmed that pathogenesis and progression of CML were closely related to the MAPK signaling pathway [27,28], endocytosis [29,30] and focal adhesion [31,32].…”