|
| Factors | Function | Expression stimulator | References |
|
| (i) Breast cancer cells |
| CXCR4 | CXCR4 binds to CXCL12 on BM endothelial cell, invades into bone, and causes Akt activation, for which activated Src is required. | ErBb2 signaling increases CXCR4 translation through activation of PI3K/Akt/mTOR pathway. | [11, 21, 22] |
| VCAM-I | VCAM-1 binds α4β7 and α4β1 (VLA-4) integrins on OCL progenitors, causing OCL differentiation and osteoclastogenesis. | VCAM-1 is increased by expressed NF-κB, α4, or VCAM-1 blocking antibodies effectively inhibiting bone metastasis. | [23, 24] |
| CD44 | CD44 binding to its receptor (hyaluronan) and its activation lead to IL-8 production in the tumor cell, which stimulates osteolysis. | High levels of CD44 expression on breast cancer cells promote their invasion and adhesion to BM endothelial cells. | [26] |
| Jagged-1 | Jagged-1 by activation Notch signaling stimulates the IL-6 expression in OB; also Jagged-1 expression activates OCL differentiation, and bone resorption occurs. | Jagged-1 expression is again activated by bone-derived TGF-β through Smad pathway during osteolytic bone metastasis.
| [22, 27–29] |
| Runx2/CBFβ | Mediates inhibition of OB differentiation by inducing antagonist of Wnt, sclerostin. | IL-11 and GM-CSF are target genes of Runx2/CBFβ as OCL activators. | [30] |
| DKK1 | Inhibits OB differentiation, the expression of OPG, and RANKL reduction. | By stimulation of DKK-1 expression in tumor cells, IL-6 inhibits Wnt-mediated osteogenesis, causing an imbalance in bone homeostasis and increased bone degradation. | [17, 31] |
| CSF-1 | The surface form by itself induces the differentiation and survival of OCL, protecting OCL against the inhibitory effect of TGF-β. | ⋯ | [32] |
| PPT-1 | It is related to homing, integration, dysfunction in BM microenvironment, and eventual metastasis. | ⋯ | [33] |
|
| (ii) Prostate cancer cells |
| Endothelin-1 | Increases the activity of OB by inhibiting DKK-1 expression by marrow stromal cells; it increases osteoblast expression type 1 collagen. | It is increased in the serum of patients with PCa metastasized to bone. | [15, 34, 35] |
| CXCR4 | Causes tumor cell homing to BM by CXCL12/CXCR4 signaling. | The absence of PTEN and the subsequent activation of PI3K/Akt pathway lead to an increase in CXCR4 expression, regulating the growth and metastasis of bone through CXCL12/CXCR4 pathway. | [20, 36] |
| Osteonectin | MMP activity, especially MMP2 that is associated with invasion and metastatic potential in cancer cells, is induced by osteonectin. | S-ErbB3 stimulates the bone to secrete osteonectin, which subsequently enhances the invasion of PC-3 PCa cells by interacting with αvβ3 and αvβ5 cell surface receptors. | [37–39] |
| Shh signaling | PCa cells expressing Shh can directly and specifically induce differentiation in preosteoblasts through a Gli1-dependent mechanism. | Ascorbic acid upregulates paracrine Shh signaling in MC3T3 preosteoblasts. Matrix collagen is formed by OB in presence of AA, potentiating Shh signaling between PCa cells and OBs, inducing OB differentiation. | [29, 40, 41] |
| TBK1 | TBK1 inhibits mTOR signaling pathway, and this inhibition induces dormancy and drug resistance in PCa cells. TBK1 enhances PCa stem-like cells and drug resistance in PCa. | Binding of PCa cell to OB in hematopoietic stem cell niche induces the expression of TBK1. | [42] |
| u-PA and uPAR | Their expression is associated with aggressive disease phenotype, progression, and metastasis to bone. | Can be used as a factor in prognosis and progression of PCa. | [43, 44] |
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