Tumor microenvironment modulation by exosomes in chronic myelogenous leukemia

Abstract

Exosomes are small vesicles of 40-100 nm diameter that are initially formed within the endosomal compartment and are secreted when a multivesicular body (MVB) fuses with the plasma membrane. These vesicles are released by many cell types including cancer cells and are considered messengers in intercellular communication. The exact function of exosomes in malignant cells has yet to be elucidated, but investigation has suggested roles in cell-to-cell communication, tumor-stroma interaction, and antigen presentation, thus potentially affecting cancer progression at different steps. Although production of exosomes by CML cells has been reported, little is known regarding the role of these vesicles in CML biology. We have demonstrated that LAMA84, a human CML cell line, releases exosomes and that the addition of those microvesicles to human vascular endothelial cells (HUVEC) affects several steps of in vitro angiogenesis including motility, cytokine production, cell adhesion, and cell signalling, as well as stimulation of angiogenesis in a nude mouse assay. Furthermore, application of exosomes isolated from blood of CML patients confirmed the data obtained with exosomes, derived from LAMA84 cells, suggesting a critical role of exosomes in angiogenesis. Interestingly, in the last years several groups have indicated that modulation of exosome release by pharmacological agents, or their use as immunomodulators may affect malignant progression. Our preliminary data show that treatment of endothelial cells with carboxyamidotriazole-orotate (CTO) may inhibit exosomes-dependent angiogenesis by interfering with signal transduction pathways activated in endothelial cells by interaction with the microvesicles.