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Figure 1. Primary tumor-secreted soluble factors in the establishment of the bone/bone marrow (BM) PMN. Lysil oxidase (LOX) crosslinks collagen and elastin in the bone/bone marrow microenvironment (BME), making the extracellular matrix stiffer and more susceptible to CTCs engraftment. Tumor cells also induce LOX secretion in bone marrow adipocytes (BMAs) as well as Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)α, angiopoietin-like 2 (ANGPTL2), and angiopoietin-like 2 (ANGPTL4), which concur to determine vascular leakiness. Moreover, BMA-derived stromal cell-derived factor 1 (SDF1) induces vascular cell adhesion molecule 1 (VCAM-1) and very large antigen 4 (VLA4) expression in endothelial cells. Prostate cancer-secreted MINDIN is able to target osteoblasts, increase their proliferation and differentiation, and increase their production of receptor-activator of nuclear factor κB ligand (RANKL), which activates osteoclastogenesis, leading to bone resorption. This causes the release of growth factors such as insulin-like growth factor 1 (IGF-1), bone morphogenic proteins (BMPs), and platelet-derived growth factor (PDGF) from the bone matrix. Primary breast tumors have been reported to secrete syndecan-1, IL-8, parathyroid hormone-related peptide (PTHrP), and heparanase (HPSE), which are all able to activate osteoclastogenesis either directly or by activating the RANK-RANKL pathway through osteoblasts. PTHrP is also able to induce CC-motif chemochine ligand 2 (CCL2) expression in osteoblasts, which summons anti-inflammatory M2 Macrophages (M2 Macs). M2 Macs, together with myeloid-derived suppressor cells (MDSCs) and t-regulatory cells (T-regs), help establish immune tolerance in the BME. Image created with BioRender.com.