Extracellular Vesicles Enhance Multiple Myeloma Metastatic Dissemination

Abstract

Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures shed by all kinds of cell types, which are released into the surrounding microenvironment or spread to distant sites through the circulation. Therefore, EVs are key mediators of the communication between tumor cells and the surrounding microenvironment or the distant premetastatic niche due to their ability to transport lipids, transcription factors, mRNAs, non-coding regulatory RNAs, and proteins. Multiple myeloma (MM) is a hematological neoplasm that mostly relies on the bone marrow (BM). The BM represents a highly supportive niche for myeloma establishment and diffusion during the formation of distant bone lesions typical of this disease. This review represents a survey of the most recent evidence published on the role played by EVs in supporting MM cells during the multiple steps of metastasis, including travel and uptake at distant premetastatic niches, MM cell engraftment as micrometastasis, and expansion to macrometastasis thanks to EV-induced angiogenesis, release of angiocrine factors, activation of osteolytic activity, and mesenchymal cell support. Finally, we illustrate the first evidence concerning the dual effect of MM-EVs in promoting both anti-tumor immunity and MM immune escape, and the possible modulation operated by pharmacological treatments.

Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis

“…Lipids are also an integral part of EVs, and several studies have described EV lipid composition. EVs are rich in cholesterol, phospholipid (phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol), sphingomyelin, glycosphingolipids, diglyceride, polyglycerol, and ganglioside GM3 [88][89][90]. Specific lipids are enriched in EVs compared with their parent cells.…”

“…Studies have shown a [90]. As part of vesicle membranes, EV lipids provide the structural rigidity and stability required during the budding process as well as the ability to protect EV cargo, promoting autocrine or paracrine signaling [89,94]. EV uptake can also be affected by lipid composition, with lipid rafts allowing the EVs to fuse into recipient cells [89].…”

“…As part of vesicle membranes, EV lipids provide the structural rigidity and stability required during the budding process as well as the ability to protect EV cargo, promoting autocrine or paracrine signaling [89,94]. EV uptake can also be affected by lipid composition, with lipid rafts allowing the EVs to fuse into recipient cells [89]. As a result of EVs' high lipid content, they have an inherent capacity to pass through biological barriers and escape from phagocytosis by the reticuloendothelial system, while being biocompatible and immunologically inert [88,95].…”

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

“…Therefore, extracellular PVT1 and especially circPVT1 may have a putative role in hematological malignancies. In MM, extracellular vesicles have a supportive role during metastatization by promoting angiogenesis, uptake at distant premetastatic niches and activation of osteolytic activity [129]. Given their known role in angiogenesis, as proved in solid tumors, and their ability to shape cellular function, as demonstrated in immune cells, we can hypothesize that PVT1 and circPVT1 may be loaded as RNA cargo in extracellular vesicles released by plasma cells, in order to instruct the tumor microenvironment (e.g.…”

Carbonic anhydrase IX as a novel candidate in liquid biopsy

“…Nanosized exosomes (70-150 nm) are the most prominent members of these so-called extracellular vesicles (EVs) and are released from body fluids such as urine, ascites, and plasma 73,74 . Moreover, they are liberated over all kinds of body cells (epithelium cells, haematopoietic cells, adipocytes, healthy and malignant cells) 75 , released in almost all cell types under physiological and pathophysiological conditions and mediate intercellular contacts 76 . A theranostic solution could be represented by the nanosized EVs, which may transmit biomarkers of diseases and/or vectors of therapeutic molecules, offering a unique opportunity to use a combination of different markers specifically expressed for tumour-derived EVs 74,76,77 .…”