## 3 Bone Stammal Niche and Metastasis
They release numerous factors that include hepatocyte growth factor (HGF), TGF-\(\beta\), stromal-derived factor 1 (SDF-1), VEGF, interleukin-6 (IL-6), in addition to MMPs that affect several hallmarks of cancer,  
Figure 2: Cross talk signaling in bone niches during bone metastasis. Immature osteoblasts express higher levels of stromal-derived factor 1 (SDF-1) and support HSC maintenance. SDF-1 is involved in the bone tropism of bone metastasizing cancers. Cancer cells expressing C-X-C chemokine receptor type 4 (CXCR4) home to bone and reside in the pre-metastatic niche. SDF-1 induces cancer cell dormancy after it anchors the cancer cells in the niche. Cancer-associated fibroblasts (CAFs) release numerous factors such hepatocyte growth factor (HGF), TGF-\(\beta\), SDF-1, VEGF, IL-6 and MMPs, affecting tumor growth, invasion, metastasis and therapy resistance. TRAP-positive osteoclasts express C-C motif chemokine ligand 22 (CCL22) which promotes bone metastasis, attracting cancer cells expressing its ligand C-C chemokine receptor type 4 (CCR4). Osteopontin (OPN) binds the extracellular matrix and stimulates HSC and osteoclast adherence to the bone matrix. OPN is a negative regulator of HSC cycling. High OPN expression has been found within metastatic cells and in the surrounding tissue stroma. Thrombospondin (TSP1) assists the cancer cell invasion. It strongly stimulates cancer cell migration, and this effect is correlated to the expression of its cellular ligand CD36, also involved in TSP1 antiangiogenic activity. including tumor growth, invasion, metastasis and therapy resistance [41; 42]. Human BM-derived mesenchymal stem cells (MSCs) stimulated with conditioned medium from breast cancer cells can acquire a CAF-like phenotype [43] (Figure 2). SDF-1 signaling seems to be implicated in tumor metastasis tropism. SDF-1 gradients regulate HSC retention within BM niches, and cancer cells expressing SDF-1 receptor (CXCR4) home to bone and reside in the pre-metastatic niche. Immature osteoblasts in the endosteal niche express higher levels of SDF-1 and support HSC maintenance [29]. SDF-1 is involved in the bone tropism of bone metastasizing cancers such as breast, ovarian, prostate and brain. Interestingly, neutralization of the SDF-1/CXCR4 axis can block prostate metastasis [44; 45; 46; 47]. It is well-known that osteoblasts produce osteopontin (OPN), that bind the extracellular matrix at the endosteal surface and stimulate HSC and osteoclast adherence to the bone matrix. In the endosteal niche, OPN is a negative regulator of HSC cycling. Increased OPN expression has been found within metastatic cells and in surrounding tissue stroma. It is thought that OPN is involved in metastatic spread of breast, prostate, colon and liver cancers [48; 49] (Figure 2). It has been well-evidenced that SDF-1 induces pro-survival signaling in CXCR4-positive AML cells. The inhibition of the SDF-1a/CXCR4 pathway led to chemo-sensitization of AML cells [50]. A relationship between SDF-1 and Notch has been found [51]. Cell surface, total protein and mRNA levels of CXCR4, the principal signaling receptor for SDF-1, were significantly decreased in Notch ligand or Delta-like ligand 4 (DII4)-transduced endothelial cells, which is attributable to a significant reduction of CXCR4 promoter activity [40]. In addition, HSC quiescence and retention in the marrow niche is facilitated by the interaction between Notch1 and jagged canonical Notch ligand 1 (JAG1) or Delta-like ligand 4 (DII4), expressed by niche cells [52]. Notch has been linked to \(\beta\)-catenin-dependent tumorigenesis. The expression of JAG1 in HSC is correlated to the mutation in the \(\beta\)-catenin gene in osteoblasts [53], and the expression levels of \(\beta\)-catenin in osteoblasts is considered as a marker for the prognosis of hematological malignancies [54; 55]. SDF-1 expression is also induced by osteopontin (OPN).