Extracellular Vesicles: A New Prospective in Crosstalk between Microenvironment and Stem Cells in Hematological Malignancies

Abstract

The bone marrow (BM) microenvironment in hematological malignancies (HMs) comprises heterogeneous populations of neoplastic and nonneoplastic cells. Cancer stem cells (CSCs), neoplastic cells, hematopoietic stem cells (HSCs), and mesenchymal stromal/stem cells (MSCs) are all components of this microenvironment. CSCs are the HM initiators and are associated with neoplastic growth and drug resistance, while HSCs are able to reconstitute the entire hematopoietic system; finally, MSCs actively support hematopoiesis. In some HMs, CSCs and neoplastic cells compromise the normal development of HSCs and perturb BM-MSCs. In response, "reprogrammed" MSCs generate a favorable environment to support neoplastic cells. Extracellular vesicles (EVs) are an important cell-to-cell communication type in physiological and pathological conditions. In particular, in HMs, EV secretion participates to unidirectional and bidirectional interactions between neoplastic cells and BM cells. The transfer of EV molecular cargo triggers different responses in target cells; in particular, malignant EVs modify the BM environment in favor of neoplastic cells at the expense of normal HSCs, by interfering with antineoplastic immunity and participating in resistance to treatment. Here, we review the role of EVs in BM cell communication in physiological conditions and in HMs, focusing on the effects of BM niche EVs on HSCs and MSCs.

Figure 1

A schematic drawing of neoplasm EV effects in BM of HMs. Tumor EVs (colored balls) can (1) render malignancy more aggressive through autocrine mechanisms via (2) the induction of a suppression of hematopoietic stem/progenitor cell (HSPC) functions and a stem cell malignant transformation and (3) modification of mesenchymal stromal/stem cells (MSCs) reducing their HSC support. On the other hand, “reprogrammed” MSCs release EVs that (4) support the proliferation of malignancy cell proliferation and (5) promote HSPC viability and clonogenicity. In addition, leukemia stem cell EVs induce proliferation and migration of malignant cells (6). Arrows turned upwards (∧) and downwards (∨) indicate an increase and a reduction, respectively.