Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

Abstract

Following their discovery at the end of the 20th century, extracellular vesicles (EVs) ranging from 50-1,000 nm have proven to be paramount in the progression of many cancers, including hematological malignancies. EVs are a heterogeneous group of cell-derived membranous structures that include small EVs (commonly called exosomes) and large EVs (microparticles). They have been demonstrated to participate in multiple physiological and pathological processes by allowing exchange of biological material (including among others proteins, DNA and RNA) between cells. They are therefore a crucial way of intercellular communication. In this context, malignant cells can release these extracellular vesicles that can influence their microenvironment, induce the formation of a tumorigenic niche, and prepare and establish distant niches facilitating metastasis by significantly impacting the phenotypes of surrounding cells and turning them toward supportive roles. In addition, EVs are also able to manipulate the immune response and to establish an immunosuppressive microenvironment. This in turn allows for ideal conditions for heightened chemoresistance and increased disease burden. Here, we review the latest findings and reports studying the effects and therapeutic potential of extracellular vesicles in various hematological malignancies. The study of extracellular vesicles remains in its infancy; however, rapid advances in the analysis of these vesicles in the context of disease allow us to envision prospects to improve the detection and treatment of hematological malignancies.

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

“…The currently available experimental strategies to characterize ExMVs include nanoparticle tracking analysis that calculates size distributions and numbers of ExMVs in suspension, electron microscopy-based approaches to visualize their structure, and flow cytometry combined with antibodies against selected surface markers [ 8 , 24 – 27 ]. Other strategies for studying molecular signatures of ExMVs are based on analysis of their cargo (mRNA species, protein, bioactive lipid content, and metabolites) by employing “omics” technologies aimed at the detection of mRNA species (transcriptomics), proteins (proteomics), lipids (lipidomics), and metabolites (metabolomics) [ 8 , 19 , 24 – 27 ]. In addition, evidence has accumulated that ExMVs also contain several extracellular signaling nucleotides - for example, adenosine triphosphate (ATP) - involved in purinergic signaling.…”

“…By analogy to physiological hematopoiesis, we learned that ExMVs also play an essential role in leukemia, and we will focus on this topic in this review. Briefly, ExMVs can affect the proliferation and survival of leukemic cells, modulate the hematopoietic microenvironment to support leukemia cell expansion, contribute to immune escape by malignant cells, and promote chemotherapy resistance [ 12 , 24 – 27 , 30 , 31 ]. On the other hand, they could play a role in diagnosing hematopoietic malignancies as they express potential biomarkers and even be modified as drug carriers for therapy [ 22 , 32 – 34 ].…”

“…These effects are mediated by surface-expressed ligands or the content of fused or internalized inside cargo. Accordingly, ExMVs may (i) interact with cell surface receptors, (ii) fuse with target cells to release their cargo into the cytosol, or (iii) they can be internalized [ 8 , 27 , 29 , 30 , 33 , 34 , 45 ]. The first two mechanisms are the most important, as internalization may lead to lysosomal degradation of ExMVs content.…”

“…Unsurprisingly, leukemic ExMVs display different molecular profiles than ExMVs derived from normal hematopoietic cells [ 24 – 27 ]. The molecular signature of leukemic ExMVs varies, depending on the type of hematological malignancy and the stage of the disease [ 24 ].…”

“…It also contains many other cells, such as fibroblasts, endothelial cells, and cells lining bone niches, providing signals supporting hematopoiesis. Evidence has accumulated that leukemia cell-derived ExMVs in BM remodel the microenvironment to favor their expansion [ 27 , 34 , 41 , 45 ]. Accordingly, they modify BM hematopoietic stem cell niches, stimulate angiogenesis, and transform BM stroma cells into leukemia-supporting cells.…”