## 3 Bone Stammal Niche and Metastasis  
The bone marrow (BM) cell microenvironment includes stem and progenitor cells, differentiated hematopoietic lineage cells, vascular cells and bone cells like osteoblasts [28]. Moreover, physiologically bone contains two stammal niches localized in the BM cavity, including the endosteal and the vascular niches [29]. The endosteal niche is localized in the internal bone shell surface [30], in particular, close to the endocortical and trabecular surfaces [29], and include two types of osteoblastic cells, the actively bone-producing osteoblasts and a type of early osteoblast termed spindle-shaped N-cadherin+ CD45-osteoblastic cells (SNO) [31]. There is a crosstalk between SNO cells and hematopoietic stem cells (HSCs), which regulate the cycle, the fate and activity of both SNO and HSC [29] (Figure 1a). During tumor metastasis, cancer cells that arrive and establish at a pre-metastatic niche take control of the physiological functions exerted by the stammal niches in order to support their own functions, varying from tumor cell dissemination to dormancy, relapse and growth [32]. [PERSON] et al. demonstrated that VEGF receptor 1 (VEGFR1)-positive BM-derived hematopoietic progenitor cells migrate and form cellular clusters in tumor-specific pre-metastatic sites [33] (Figure 2). Figure 1: Bone stammal niches (adapted with permission from [29], MDPI, 2017). (**a**) The endosteal niche includes two types of osteoblastic cells, the actively bone-producing osteoblasts (OB) and a type of early osteoblast termed spindle-shaped N-cadherin+ CD45- osteoblast cells (SNO). The intercommunication existing between SNO cells and hematopoietic stem cells (HSCs) regulate the cycle, the fate and activity of both SNO and HSC. In the endosteal niche, stem cells, progenitor cells, stromal cells, growth factors and extracellular matrix (ECM) molecules participate to the regulation of hematopoiesis. (**b**) HSC niche is localized in the center of the bone marrow (BM) cavity close to the sinusoidal endothelium to form the so-called vascular niche. The blood vessels of the BM participate in the regulation of hematopoiesis as well as stem cell mobilization and homing. Endothelial cells are surrounded by adventitial cells, also called CXCL12-abundant reticular (CAR) cells. The closeness between sinusoidal endothelial cells and HSCs is very important for their maturation and for the hematopoietic process. Many leukemia cells, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), produce high levels of VEGF and express VEGF receptors (VEGFRs) [34; 35]. VEGFR1 is involved in targeting of these cells within the BM, and in the regulation of their survival, as well as their passage into the circulation [36]. Cancer cells secrete numerous factors, including VEGF and placental growth factor (PIGF), that induce local changes in tumor stroma, and activate the BM-derived cells to support angiogenesis. VEGFR signaling leads to the recruitment of hematopoietic stem cells (HSCs) and endothelial precursor cells (EPCs) expressing VEGFR2 to neoangiogenic sites in the tumor [36]. We have previously discussed the crucial role of osteoblasts located in the endosteal niche in the regulation of the activity and fate of HSCs [29]. HSCs which adhere to osteoblasts express angiopoetin receptor-2 (Tie-2), while the lining cells in BM synthesize Ang-1. The activation of Tie-2 by Ang-1 induces the adhesion of the two cell types and Ang-1 enhances the survival of HSCs [37]. In addition, it has been demonstrated that another mesenchymal-derived cell-type resident in the endosteal niche involved in the formation and progression of bone metastasis includes fibroblasts. CAFs form a supportive microenvironment that promotes tumor progression by regulating ECM deposition, recruitment of inflammatory mediators and epithelial differentiation [38; 39]. CAFs are one of the most abundant stromal cell types in breast cancer and are associated with poor prognosis [40].