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Figure 2. Proposed effects of tumor-derived extracellular vesicles (EVs) in the establishment of the bone/bone marrow PMN. Tumors secrete extracellular vesicles (EVs) that reach the bone/bone marrow microenvironment (BME). Prostate cancer (PrCa) can induce osteoblast (OB) proliferation and differentiation through their EVs, by shuttling phospholipase D2 (PLD2), as well as miR-21 and miR-141-3p. They can also induce mesenchymal stromal cells (MSCs) osteogenic differentiation through miR-940. This induces extensive osteoblastic lesions. Non-small cell lung cancer (NSCLC) and multiple myeloma (MM) EVs induce osteoclastogenesis through amphiregulin (AREG), which activates the receptor-activator of nuclear factor κB (RANK)-RANK ligand (RANKL) pathway. Breast cancer (BrCa) EVs induce osteoclast formation from precursors directly and through osteoblastic production of RANKL (membrane bound and soluble sRANKL), interleukin-6 (IL-6), and Lipocalin-2. BrCa can also induce the release of “educated” OB-EVs, which express RANKL on their surface, thus further increasing osteoclast formation and bone resorption. Educated OB-EVs also increase in vitro and in vivo angiogenesis. Image created with BioRender.com.