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. 2019 Jan 15;3(3):e10126. doi: 10.1002/jbm4.10126

Figure 1.

Figure 1

Metastatic progression in the bone. (A) Tumor‐derived factors promote the formation of a premetastatic niche in the bone prior to tumor cell dissemination. Factors such as lysyl oxidase (LOX) and C‐C motif chemokine ligand 2 (CCL2) disrupt normal bone homeostasis thereby favoring tumor cell colonization. (B) Disseminated tumor cells (DTCs) enter the circulation and can eventually home to the bone via microenvironmental signals including CXCL12:CXCR4 and E‐selectin. (C) Following extravasation, interaction with resident bone cells and signaling molecules such as leukemia inhibitory factor receptor (LIFR), p38, and thrombospondin‐1 (TSP1) maintain tumor cells in a dormant state. (D) Emergence of DTCs from dormancy results in the outgrowth into overt metastases. Tumor cell proliferation and osteolytic bone destruction is mediated by parathyroid hormone‐related protein (PTHrP), receptor activator of NFκB ligand (RANKL), and vascular cell adhesion molecule‐1 (VCAM‐1). The growth of neovasculature within the metastasis produces transforming growth factor beta 1 (TGFβ1) and periostin to further promote the proliferation of metastatic tumor cells. CAF = cancer‐associated fibroblast; CXCL12 = CXC Chemokine Ligand 12; LOX = lysyl oxidase; CCL2 = C‐C Motif Chemokine Ligand; IL‐6 = Interleukin‐6; DKK1 = Dickkopf WNT Signaling Pathway Inhibitor 1; CXCR4 = CXC Motif Chemokine Receptor 4; CX3CL = CX3C motif Chemokine Ligand; CX3CR = CX3C Motif Chemokine Receptor; TSP1 = Thrombospondin‐1; LIFR = Leukemia Inhibitory Factor Receptor; STAT3 = Signal transducer and activator of transcription 3; MSK1 = Ribosomal Protein S6 Kinase A5; NR2F1= Nuclear Receptor Subfamily 2 Group F Member 1; TAM receptors = TYRO3 Protein Tyrosine Kinase, AXL Receptor Tyrosine Kinase, MER Proto‐Oncogene Tyrosine Kinase; p38 = Mitogen Activated Protein Kinase 14; ERK = Extracellular‐signal Regulated Kinase; BMP = Bone Morphogenetic Protein; TGFb = Transforming Growth Factor Beta; GAS6 = Growth Arrest Specific 6; CDH1 = E‐cadherin; CDH2 = N‐cadherin; PTHrP = Parathyroid Hormone related Protein; PTHR1= Parathyroid Hormone Receptor 1; RANK = TNF Superfamily Member 11; VCAM1 = Vascular Cell Adhesion Molecule 1.