###### Abstract  
In post-natal life, stem cells contribute to the preservation of many tissues. In adults, stem cells remain localized, in particular, specialized microanatomical areas named as niches, which are crucial in the control of stem cell quiescence and activity through the production of many regulatory signals. Bone physiologically includes both the endosteal niche and the vascular niche, which are involved in the attraction, retention and release of the residing stem cells during the formation of new vessels as well as in the control of the differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. In tumors, cancer cells are able to take control of the niches to support all the stages of the tumorigenesis, transforming them in the so-called pre-metastatic and metastatic niches. Hence, there is emerging importance of the interactions between cancer cells, bone cells and niches in driving metastatic progression. This review article summarizes the literature data concerning the role of bone vascular and endosteal niches in the regulation of bone metastasis, focusing on their cellular and molecular interactions and the potential therapeutic approaches. bone staminal niche; bone metastasis; endosteal niche; pre-metastatic niche; vascular niche +
Footnote †: journal: Medical  
It is well-known that the tumor microenvironment (TME) and metastatic process are interconnected. TME is complex tissue environments in which the tumor cells are surrounded by various types of cells, extracellular matrix (ECM) components and a vascular network involved in the regulation of tumor initiation, progression and metastasis [7; 8]. The process leading to organ tropism in tumor metastasis has been extensively investigated. Up to now the \"seed and soil\" hypothesis elaborated by [PERSON] remain valid. He proposed that metastasis is the result of favorable interactions between metastatic tumor cells (\"seed\") and the target organ microenvironment (the \"soil\") [9; 10]. In addition to inducing tumor growth, these interactions can impair the function of bone cells, leading to increased osteoclast-mediated bone resorption or excessive increased bone formation. In this context, bone metastases can be classified into ostecolytic, osteoblastic and a mixed phenotype of both [11; 12]. The osteolytic lesions are characterized by the destruction of normal bone by osteoclasts and not due to the direct involvement of tumor cells. During this process, parathyroid hormone-related peptide (PTHrP) and the receptor activator of nuclear factor-\(\kappa\)B ligand (RANKL) play a crucial role in osteolytic bone metastasis [13]. It is not clear if the bone microenvironment induces cancer cells to express PTHrP or the latter have an intrinsic higher PTHrP expression. Osteoblastic metastasis is characterized by deposition of new bone. Many factors are involved during osteoblastic metastasis, in particular, transforming growth factor (TGF), bone morphogenetic proteins ( BMPs) and endothelin-1 [14]. In mixed metastasis, present in breast cancer [13; 15], gastrointestinal cancer and squamous cancer [16; 17], both types of lesions are present. The most common skeleton metastases are the osteolytic bone lesions that are typical of breast and lung carcinoma as well as hematological malignancies such as multiple myeloma. Although some cancer cells such as the breast cancer cells exert osteoclast-like activities and are able to resorb bone [18], the bone resorption process caused by osteolytic metastases is due to the positive modulation of osteoclasts by cancer cells [19]. It has been established that the secretion of ECM-modifying enzyme lysyl oxidase (LOX) in osteolytic lesions is correlated to the hypoxia, which is essential for the formation of PMN [20]. Moreover, PTHrP [21], interleukin-6 (IL-6) [22] and matrix metalloproteinases (MMPs) [22] are known to stimulate osteoblasts to release RANKL, which in turn induces osteoclast differentiation.