Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. therapeutic targets that could be utilized to treat bone metastasis. strong class=”kwd-title” Keywords: bone, metastasis, tumor microenvironment, stromal cells, mesenchymal stem cells, cancer-associated fibroblasts, metastatic niche, dormancy 1. Introduction Metastasis is usually a major challenge in oncology clinics that contributes to 80% of cancer-associated deaths. Bone is the most common metastatic site for many cancers, including breast, prostate, and Dynarrestin lung cancers, with approximately 70% of patients with advanced disease exhibiting bone metastasis [1,2,3]. Patients with bone metastasis not only experience substantial morbidity such as pain, increased risk of fracture, and hypercalcemia, but also exhibit reduced a 5-12 months survival rate of 26% and 33% in breast and prostate cancer, respectively [4]. While palliative Dynarrestin treatments such as anti-osteolytic bisphosphonates are available to improve such symptoms and lessen the morbidity associated with bone metastasis, these do not significantly enhance survival. Bone metastases are often resistant to anti-tumor treatments and therefore there remains no remedy [5]. Tumors have previously been described as a wound that does not heal displaying many features similar to the wound healing response. These include the infiltration of immune cells and mesenchymal stromal cells, vasculature, and non-cellular components Dynarrestin such as the extracellular matrix, which together make up the tumor microenvironment (TME). It is now evident that this TME plays an important role in tumor development by establishing interactions between these host components and the tumor cells [6]. One important component of the TME is usually mesenchymal stromal cells, which comprise mesenchymal stem cells (MSCs), pericytes, fibroblasts, and osteoblasts. These stromal cells have been shown to promote tumor development, metastasis, and therapy resistance through several pro-tumorigenic effects including: enhanced tumor growth via growth factor release and stimulation of angiogenesis; promoted migration and invasion by the induction of the epithelial-to-mesenchymal transition and production of matrix metalloproteinases (MMPs); and immune evasion via interactions with the immune cells to create an immunosuppressive environment [7,8,9]. However, this research is mostly limited to the primary Sirt2 tumor. Bone metastatic cancers often have already spread at the time of diagnosis, with disseminated tumor cells (DTCs) being detected in the bone of many patients. These DTCs are drug resistant and can give rise to secondary bone metastasis years after the initial resection or treatment of the primary tumor [10]. This suggests that the pro-tumorigenic effects of the mesenchymal stromal cells within the primary tumor may have already occurred before initial diagnosis; therefore, it may be more appropriate to therapeutically target the DTCs at the secondary site rather than prevent the dissemination from the primary tumor in the first place. This review will therefore focus on the role of the mesenchymal stromal cells within secondary bone metastasis after the tumor cells have reached the site. Initially the mesenchymal stromal cells contribute to a niche that facilitates homing and colonization. Within this niche, the tumor cells can survive and remain dormant, and may eventually reactivate and grow to establish a metastatic lesion within the bone. We will discuss the molecular mechanisms that regulate these processes and spotlight potential therapeutic targets that may serve as a way to combat bone metastasis in the clinic. 2. Mesenchymal Stromal Cells within the Tumor Microenvironment The mesenchymal stromal compartment of the TME consists of MSCs, pericytes, fibroblasts, and osteoblasts, which are also Dynarrestin found in different regions of the bone and can be defined by different cell markers (Physique 1). MSCs are multipotent cells that play a role in tissue maintenance and the regeneration of connective tissues including bone, cartilage, and adipose tissue by differentiating into osteoblasts, chrondocytes, and adipocytes, respectively [7,8]. They are also recruited to.