Table 1.
Factors contributing to bone metastasis.
| Factor | Functional Description | Reference |
|---|---|---|
| Signaling/Secreted Factors | ||
| ADM | Potentiates osteolytic responses in bone to metastatic breast cancer | [92] |
| ANGPTL2 | Up-regulates CXCR4 expression in tumor cells, enhancing responsiveness of breast cancer cells to bone tissues secreting CXCL12 | [93] |
| DKK1 | Promotes bone metastasis by regulating canonical WNT signaling of osteoblasts | [94] |
| IL-1β | Stimulates breast cancer colonization by inducing NFkB/CREB-Wnt signaling | [95] |
| IL-6 | Inhibition of IL-6 reduces MDA-231 bone metastasis by inhibiting cell proliferation and decreasing expression of P-Stat3, VEGF, and RANK | [96] |
| IL-11 | Promotes bone metastasis through JAK1/STAT3 signaling pathway in BoM-1833 cells | [97] |
| ITGBL1 | Facilitates recruitment, residence, and growth of breast cancer in bone | [98] |
| Jagged1 | Tumor-derived ligand that activates Notch signaling in bone, promoting IL-6 secretion and subsequent osteolytic bone metastasis | [63,99] |
| OPN | Enhances ability of CD44+ breast cancer cells to migrate to the bone, potentially through activation of WINK-1 and PRAS40-related pathways | [100] |
| Sclerostin | Promotes cell migration, invasion, and bone osteolysis | [60] |
| VCAM-1 | Promotes metastasis by interacting and recruiting α4β1-positive osteoclast progenitors | [101] |
| Transcription Factors | ||
| HIF-1α | Promotes metastatic spread by upregulating PTGS2/COX-2 and by increasing expression of CXCL12 in osteoprogenitor cells | [102,103] |
| Runx2 | An essential regulator of skeletal development, Runx2 is highly expressed in breast cancer skeletal metastases, and is associated with tumor-induced osteolysis. Runx2 activity is promoted via the PI3K/AKT signaling pathway. Evidence shows that expression in bone metastasis is regulated by miR-135 and miR-203. Functions also in increasing cell proliferation via disrupting growth-arresting acini structures, and promoting cell survival by enhancing the autophagic process. | [20,42,48,49,50,51,52,54,58,59,85] |
| GLI-2 | Increases secretion of osteolytic factors such as parathyroid hormone-related protein (PTHrP) | [46,47] |
| STAT3 | Contributes to migration, invasion, and angiogenesis | [104] |
| Micro RNA | ||
| miRNA 135 miRNA 203 |
Both show diminished expression in bone metastatic MDA-231 cells, and are related to aberrant expression of Runx2 | [88] |
| miRNA 218-5P | Highly expressed in bone metastatic breast cancer cells, functioning to promote WNT signaling and enhance osteolysis | [89] |
| Enzymatic Proteins | ||
| ADAMTS1 MMP1 |
Modulate bone microenvironment in favor of osteoclastogenesis and bone metastasis | [105] |
| MMP13 | Upregulation contributes to osteoclast differentiation by activating MMP-9 and promoting cleavage of galectin-3 | [106] |
| MFAP5 | Increases and accelerates bone metastasis, possibly by increasing expression of MMP2, MMP9, and activating the ERK signaling pathway | [107] |
| Receptors and Growth Factors | ||
| βAR | βAR stimulation in osteoblasts may activate bone marrow vessels to favor skeletal engraftment of breast cancer cells | [108] |
| BMPR1a | BMPR1a promotes osteolytic metastasis of breast cancer cells by promoting RANKL production via the p38 pathway | [109] |
| FGFR1/FGF | FGFR1 activation by tumor cell-derived FGF ligands enhance osteoclast function, contributing to metastatic lesions | [110] |
| Notch | Activation of Notch signaling in bone microenvironment via tumor-derived Jagged1 promotes osteoclast differentiation and facilitates metastasis by initiation EMT. Activation via tumor-derived Galectin-3 has been shown to inhibit osteoblast differentiation | [63,99,111] |
| IGF-1R/IGF | IGF-1R activation by bone-derived IGF stimulates bone metastasis via activation of the Akt/NF-κB signaling pathway | [112] |
| C-Met/HGF | C-Met and cognate ligand HGF expression in bone correlates with bone metastasis | [113] |
| RANK/RANKL | RANKL expression and RANK activation is induced by tumor-derived factors, promoting osteoclast activity and increasing bone invasiveness | [114] |
| TGF-β | TGF-β released in bone matrix upon tumor-induced osteolysis further stimulates bone metastatic cells to secrete factors driving osteolytic bone destruction | [115] |
| VEGF | VEGF is expressed strongly in breast cancer metastases, and in the presence of RANKL can stimulate formation of osteoclasts | [116] |
| Autophagy | ||
| ATG7 ATG12 |
ATG7 and ATG12 inhibition in MDA-231 cells resulted in decreased colony formation and proliferation | [77] |
| Rab5a | Rab5a expression is elevated in metastasized 1833 cells, and may be related to cell survival by triggering autophagy and autophagosome sealing | [84] |
| Chemokines | ||
| COX-2/CXCR2 | CXCR2 enhances breast cancer metastasis to bone by suppressing AKT1 and activating COX-2 | [117] |
| CXCL10/CXCR3 | CXCL10/CXCR3 axis contributes to breast cancer metastasis and osteoclast activation in 4T1 cells | [118] |
| CXCL12/CXCR4 | CXCL12/CXCR4 axis promotes breast cancer metastasis to tissues expressing high levels of CXCL12 | [119] |
Tumor and bone-derived factors contributing to bone metastasis of breast cancer cells. Abbreviations: Signaling and Secreted Factors: ADM (adrenomedullin), ANGPTL2 (angiopoietin-related protein 2), DKK1 (Dickkopf-related protein 1), IL (interleukin), ITGBL1 (integrin subunit beta like 1), OPN (osteopontin), VCAM1 (vascular cell adhesion protein 1). Transcription Factors: HIF-1α (hypoxia-inducible factor), Runx2 (runt-related transcription factor 2), STAT3 (signal transducer and activator of transcription 3). Enzymatic Proteins: ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1), MMP (matrix metalloproteinase), MFAP5 (microfibrillar-associated protein 5). Receptors and Growth Factors: βAR (beta adrenergic receptor), BMPR1a (bone morphogenetic protein receptor type 1a), FGF (fibroblast growth factor), FGFR1 (FGF receptor 1), IGF (insulin-like growth factor), IGF-1R (IGF 1 receptor), C-Met (c-Met tyrosine kinase receptor), HGF (hepatocyte growth factor), RANK (receptor activator of nuclear factor κ B), RANKL (RANK ligand), TGF- β (transforming growth factor beta), VEGF (vascular endothelial growth factor). Autophagy: ATG (autophagy related), Rab5a (Ras-related protein Rab-5a). Chemokines: COX-2 (cyclooxygenase-2), CXCL (C-X-C motif chemokine ligand), CXCR (C-X-C motif chemokine receptor).