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  • br Homing of DTCs to the HSC


    Homing of DTCs to the HSC niche The HSC niche is a complex microenvironment comprised of many cell types, including endothelial cells, adipocytes, osteoclasts, osteomacs, and clemastine of osteoblastic lineage [5]. A healthy HSC niche provides homing signals to healthy HSCs in order to promote their normal function [6]. Shiozawa et al. [7] demonstrated that increasing the number of HSC niches promoted increased number of bone marrow DTCs, which indicated these same homing signals can be exploited in PCa metastasis. Two important mediators of the HSC microenvironment are the chemo-attractant stromal derived factor-1 (SDF-1 or CXCL12) and the cell attachment factor (Annexin2 or ANXA2). CXCL12 regulates HSC homing to the bone marrow as well as mobilization into circulation, while ANXA2 is likely involved in HSC binding to the osteoblastic niche, and may act as an anchor of CXCL12 and aid in localization to the niche [8]. Recently, it was shown that bone marrow stromal cells expressing enhanced levels of CXCL12 and ANXA2 increases recruitment of PCa cells into the bone marrow, promotes proliferation of PCa cells, and protects PCa cells from chemotherapy induced apoptosis [9]. These data suggest that DTCs may home to the HSC niche using similar mechanisms to the HSCs themselves in the regulation of cell fate.
    DTC dormancy in the HSC niche The concept of a dormancy supportive/permissive microenvironment in the bone marrow is an increasingly important and complex area of investigation in clinical oncology due to the general mechanism by which chemotherapeutics act to target mitotic cells [10]. There are many mechanisms by which DTC mitotic cycling is affected including regulation of the immune system, angiogenesis/nutrients, tumor extracellular matrix, and hormones [11]. In the HSC niche, cancer cells are subject to HSC quiescent signaling mechanisms, and a number of possible contributing chemokines have been identified [7,12]. DTC dormancy can be achieved through lack of activating signals (e.g. Wnt, Notch) or directly due to inhibitory signals (BMPs) [13]. Aguirre-Ghiso et al. [14] demonstrated that the balance between p38 and ERK, both mitogen activated kinases (MAPKs), affect DTC mitotic state. When ERK is elevated compared to p38, proliferation is favored; conversely, elevation of p38 compared to ERK favors quiescence. The balance of ERK and p38 in vivo is further regulated by other ligands: down-regulation of urokinase receptor (uPAR) results in an ERKLow/p38High signaling ratio, inducing proliferative behavior in squamous carcinoma cells (HEp3) [15]. BMP7 has also been demonstrated to induce dormancy in PCa cells through the p38 MAPK pathway [16]. Other HSC-mediated factors, such as low oxygen [17], angiogenic [18], or additional secreted factors can also control dormancy. Shiozawa et al. [19] reported that growth arrest specific-6 (GAS6), a ligand of TYRO3, AXL, and MER tyrosine kinase receptors produced by osteoblasts in the HSC niche, supported PCa cell dormancy with increased survival and additionally prevented proliferation. Additionally, angiogenic simulators c-myc, vascular endothelial factor (VEGF), and fibroblast growth factor 2(FGF2) may be involved in exit of DTCs from dormancy [20,21]. Understanding the mechanisms of DTC dormancy may lead to better targeted therapies for metastatic disease.
    The role of DTCs in niche formation Following localization to the bone marrow, DTCs or their progeny can have osteoblastic or osteolytic effects, or both activities [22]. Osteoblastic lesions stimulate osteoblast formation and promote bone formation, albeit poorly woven bone [4]. Osteolytic lesions stimulate osteoclastic activity, which results in bone loss. In the instance of PCa, the impact of DTCs have been observed to be both osteoblastic and osteolytic in nature [23]. Joseph et al. [24] demonstrated that hematopoietic progenitor cells (HPCs) from mice inoculated with LNCaP-derived C4-2B induced osteoblastic differentiation of bone marrow stromal cells in co-culture through production of BMP-2. Conversely, these authors reported HSCs from mice inoculated with the PCa cell line, PC3, induced osteoclastic activity resulting in predominantly osteolytic lesions through an IL-6 mediated signaling pathway. Applications of this research include using HSC/HPC targeted therapy to limit the effects of bone metastasis. However, more research is needed to understand the precise mechanisms through which metastatic lesions may direct niche formation.