Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression

Abstract

Multiple myeloma (MM) pathogenesis and progression largely rely on the cells and extracellular factors in the bone marrow (BM) microenvironment. Compelling studies have identified tumour exosomes as key regulators in the maintenance and education of the BM microenvironment by targeting stromal cells, immune cells, and vascular cells. However, the role of MM exosomes in the modification of the BM microenvironment and MM progression remains unclear. Here, we explored the functions of MM exosomes in angiogenesis and immunosuppression in vitro and in vivo. Murine MM exosomes carrying multiple angiogenesis-related proteins enhanced angiogenesis and directly promoted endothelial cell growth. Several pathways such as signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase, and p53 were modulated by the exosomes in endothelial and BM stromal cells. These exosomes promoted the growth of myeloid-derived suppressor cells (MDSCs) in naive mice through activation of the STAT3 pathway and changed their subsets to similar phenotypes to those seen in MM-bearing mice. Moreover, MM exosomes up-regulated inducible nitric oxide synthase and enhanced the immunosuppressive capacity of BM MDSCs in vivo. Our data show that MM exosomes modulate the BM microenvironment through enhancement of angiogenesis and immunosuppression, which will further facilitate MM progression. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Endothelial progenitor cells in hematologic malignancies

“…A recent study confirmed the angiogenic activity of myeloma-derived exosomes, suggesting that these microvesicles vehiculate a variety of angiogenic cytokines into endothelial cells (97). These studies showed that multiple myeloma exosomes display pro-angiogenic activity both in vitro and in vivo.…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…Prostate cancer exosomes, expressing transforming growth factor beta (TGFβ), can activate fibroblasts Multiple myeloma, ovarian [131,134] A selected overview of pro-angiogenic factors previously identified on EV. Association of pro-angiogenic proteins with EV has been demonstrated in multiple cancers, but the precise involvement of some such proteins in prostate cancer remains unclear.…”

Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells

“…Exosomes contain receptors on their lipid bilayer membrane and carry proteins, lipids, mRNAs, miRNAs, and small DNA fragments inside to protect them from degradation (Raimondo et al, 2011; Hwang, 2013; De Veirman et al, 2016; Wang et al, 2016a). Exosomes can be distinguished by size and specific surface markers including TSG101, Alix, Flotillin-1 CD63, CD9, among other EVs (Schorey and Bhatnagar, 2008; Soltani et al, 2015; Tang and Wong, 2015; Yu et al, 2015).…”

“…Astrocyte-derived exosomes transfer the miR-17~92 cluster to suppress PTEN gene in brain tumors (Zhang et al, 2015). Malignant cells also secrete large amount of exosomes to promote endothelial cell proliferation and enhance angiogenesis, which facilities tumor progression (Umezu et al, 2014; Wang et al, 2016a). Cancer cell-derived exosomes can also induce immunosuppression in the tumor microenvironment (Chalmin et al, 2010; Wang et al, 2016a).…”