Extracellular vesicle-mediated cell-cell communication in haematological neoplasms

Abstract

Crosstalk between bone marrow tumour cells and surrounding cells, including bone marrow mesenchymal stromal cells (BM-MSCs), endothelial cells and immune cells, is important for tumour growth in haematological neoplasms. In addition to conventional signalling pathways, extracellular vesicles (EVs), which are endosome-derived vesicles containing proteins, mRNAs, lipids and miRNAs, can facilitate modulation of the bone marrow microenvironment without directly contacting non-tumourous cells. In this review, we discuss the current understanding of EV-mediated cell-cell communication in haematological neoplasms, particularly leukaemia and multiple myeloma. We highlight the actions of tumour and BM-MSC EVs in multiple myeloma. The origin of EVs, their tropism and mechanism of EV transfer are emerging issues that need to be addressed in EV-mediated cell-cell communication in haematological neoplasms.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

Keywords: bone marrow mesenchymal stromal cells; extracellular vesicles; hypoxia; leukaemia; miRNA; multiple myeloma.

Figure 1.

Bone marrow microenvironment in haematological neoplasms. The bone marrow microenvironment is located in bone. Two types of niches, the endosteal niche and vascular niche, are located adjacent to the bone cortex. Tumour cells secrete extracellular vesicles (small green circles) towards their surrounding cells such as bone marrow mesenchymal stromal cells (BM-MSCs), endothelial cells and immune cells. Various types of cell–cell communication are assumed, such as tumour cells to BM-MSCs, tumour cells to endothelial cells, tumour cells to immune cells, and others. MDSC, myeloid-derived suppressor cell; NK, natural killer; RBC, red blood cell.

Figure 2.

Hypoxia and angiogenesis in leukaemia. Human umbilical vein cells (HUVECs) were cultured with or without extracellular vesicles (EVs) secreted from a human leukaemia cell line (K562). The cells were cultured for 24 h and then EVs were collected. In normoxia, tube formation of HUVECs was increased in the presence of K562-derived EVs compared with control HUVECs (middle). When EVs obtained from K562 cells cultured under hypoxic conditions (K562-EV-hypoxia) were added to HUVECs, tube formation was much more prominent (bottom). These findings indicate possible roles of EVs, hypoxia and angiogenesis in leukaemia.

Figure 3.

Cell–cell communication by extracellular vesicles in multiple myeloma. Massive proliferation of abnormal plasma cells is shown in the centre. The centre of the mass has pale blue plasma cells, indicating the hypoxic state. In addition to conventional signalling pathways, such as direct cell adhesion and soluble factors, either extracellular vesicles (EVs) derived from multiple myeloma (MM) cells (MM-EVs; small green circles) or EVs derived from bone marrow mesenchymal stromal cells (BM-MSC-EVs; small orange circles) modify the behaviour of recipient cells as follows. MM-EVs modulate BM-MSCs and induce a favourable microenvironment for MM cells. Conversely, BM-MSC-EVs also induce MM cell growth, survival and drug resistance (bottom right). MM-EVs induce angiogenesis. In a long-lasting hypoxic state, EV-miR-135b acts as a mediator of angiogenesis through the FIH-1/hypoxia-inducible factor-1 signalling pathway (bottom left). BM-MSC-EVs interact with myeloid-derived suppressor cells (MDSCs), and MM-EVs modulate immune cells, such as natural killer (NK) cells, resulting in immunosuppression (top right). MM-EVs activate osteoclasts which may be linked to osteolysis in MM (top left).