Table 1.
Factors Controlling Metastatic Progression in the Bone
| Function | Protein Interaction | Reference(s) | |
|---|---|---|---|
| Pre‐metastatic Niches | Disrupt bone homeostasis to promote colonization | LOX | 25 |
| CCL2 | 25, 26 | ||
| IL‐6 | 27‐29 | ||
| JAG1 | 30 | ||
| DKK1 | 31 | ||
| Promote colonization | Extracellular vesicles (MET proteins) | 32‐38 | |
| Metastatic Homing | Tumor‐derived chemoattractants for bone marrow derived cells | CXCL16: CXCR6 | 46 |
| Bone‐derived chemoattractants for tumor cells | CXCL12: CXCR4 | 43‐45 | |
| Promote endothelial cell adhesion | CXCL12: CXCR4 | 47‐49 | |
| CD62E | 52 | ||
| CX3CL1: CX3CR1 | 53, 54 | ||
| ANXA2: ANXA2R | 55 | ||
| Pre‐exisiting Niches | Interaction with bone marrow cells | Competition of tumor cells with HSCs for niche occupancy | 56 |
| CDH1 (tumor cells) and CDH2 (osteoblasts) | 57 | ||
| Integral αvβ3 | 58‐62 | ||
| CD62E | 64 | ||
| CXCL12: CXCR4 | 64 | ||
| CD146, CXCR4 | 65 | ||
| Tumor dormancy | Regulate tumor dormancy | TSP1 | 63 |
| BMP7 | 72 | ||
| TGFβ2 | 73, 74 | ||
| GAS6 | 75, 76 | ||
| ATRA | 77 | ||
| uPAR | 78, 79 | ||
| p38high/ERKlow signaling | 74, 8O, 82, 83 | ||
| MSK1 | 81 | ||
| Gas6: Tyro3, Axl, MERTK | 75, 76 | ||
| LIFR, PTHrP | 86‐88, 109 | ||
| Epigenetic modifiers (NR2F1, TGFβ2, DXMT1) | 77, 82, 83 | ||
| Metastatic outgrowth | Enhance tumor cell proliferation | PTHrP, RANKL, TGFβ | 94, 95‐100 |
| VCAM‐1 | 110 | ||
| SRC | 17 | ||
| TGF‐βl, periostin (endothelial‐derived) | 63 |
LOX = lysyl oxidase; CCL2 = C‐C motif chemokine ligand 2; IL6 = interleukin‐6; JAG1 = jagged1; DKK1 = Dickkopf WNT signaling pathway inhibitor 1; CXCL = CXC chemokine ligand; CXCR = CXC motif chemokine receptor; CD62E = E‐selectin; CX3CL = CX3C motif chemokine ligand; CX3CR = CX3C motif chemokine receptor; ANXA2 = annexin II; ANXA2R = annexin A2 receptor; CDH1 = E‐cadherin; CDH2 = N‐cadherin; CD146 = melanoma cell adhesion molecule; TSP1 = thrombospondin‐1; BMP7 = bone morphogenetic protein 7; TGFβ = transforming growth factor beta; GAS6 = growth arrest specific 6; ATRA = all‐trans retinoic acid; uPAR = urokinase plasminogen activator receptor; p38 = mitogen‐activated protein kinase 14; ERK = extracellular‐signal regulated kinase; MSK1 = ribosomal protein S6 kinase A5; Tyro3 = TYRO3 protein tyrosine kinase; Axl = AXL receptor tyrosine kinase; MERTK = MER proto‐oncogene tyrosine kinase; LIFR = leukemia inhibitory factor receptor; NR2F1 = nuclear receptor subfamily 2 group F member 1; DNMT1 = DNA methyltransferase 1; PTHrP = parathyroid hormone‐related protein; RANKL = TNF superfamily member 11; VCAM1 = vascular cell adhesion molecule 1; SRC = SRC proto‐oncogene.