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  • 1-NM-PP1 In addition to CAF in the primary

    2019-06-27

    In addition to CAF in the primary tumour microenvironment, it is tempting to speculate that fibroblasts within the bone itself may play a role in the establishment of metastatic deposits. Fibroblasts form a major component of the bone marrow stroma and regulate haematopoiesis by secreting a range of cytokines, including those known to be involved in metastatic growth in bone [21]. Bone remodeling provoked by tumour growth (particularly in osteolytic lesions) causes the release of proteins such as TGFβ that may activate fibroblasts to secrete cytokines favouring further tumour growth [4,22].
    Future perspectives
    Conflicts of interest
    Metastatic cancer cells circulate through every organ via blood vessels, and can infiltrate some more than others to eventually cause lethal pathological dysfunction. Metastasis to distant organs, including liver, 1-NM-PP1 and the skeleton is nowadays the main cause of death in patients treated for breast or prostate cancer. Metastasis to the skeleton is very common, as 73% of patients with terminal breast and prostate cancers have evidence of metastatic bone disease . This leads to predominantly lytic lesions causing pain, hypercalcemia, fractures, and spinal cord/nerve compression. Metastasis may remain confined to the skeleton, and eventual cause of mortality is almost entirely due to skeletal complications and their treatments. The 5-year survival rate of women diagnosed with bone metastasis is 22% (National Cancer Institute\'s SEER database). There are multiple reasons why the skeleton is a preferential organ for metastasis. First, it is a large and well-vascularized tissue, with a fenestrated sinusoidal vasculature that may favor circulating cancer cell arrest and establishment into the skeleton, especially for cancer cells metastasizing as cluster. Host cells residing within the bone marrow environment also secrete a number of cytokines and extracellular matrix proteins that promote the homing or retention of metastatic cancer cells within the skeleton, as well as their survival, dormancy and drug resistance . Skeletal metastasis in women with advanced breast cancer often leads to death within a couple of years. Though the above mentioned skeletal complications and their treatment contribute to this high mortality rate, additional mechanisms are likely to be involved. The fact that the skeleton is an endocrine organ that can impact the function of other organs, including the pancreas , the gonads and muscles for instance suggests that skeletal metastasis, especially at late stages, can disrupt general body homeostasis, thereby leading to the morbidities afflicting relapsing patients. Because of the irreversible and complex nature of late stage disease, earlier detection of metastatic events is likely to result in higher treatment efficacy and to increase the survival of these patients. Thus, characterizing the early determinants of skeletal metastasis is necessary to uncover novel targets and strategies to eradicate metastatic cells at early stages.
    Macrophages, osteomacs and osteoclasts Macrophages (Macs) are immune cells derived both from embryonic precursors and circulating CD14+ monocytes which originate from the bone marrow [1]. Cell fate mapping studies in mice on adult microglia, bone marrow cells, alveolar macrophages and macrophages in mouse inflammation [2] have further demonstrated that tissue resident Macs can proliferate in situ, thereby bypassing the need of differentiation from newly recruited monocytes. Macs adopt different polarization/activation statuses as response to environmental stimuli and perform distinct physiologic functions from phagocytosis to antigen presenting, wound healing, immune regulation, tissue vascularization and inflammation [3]. Mac polarization spans a broad spectrum of intermediate statuses, with M1 or classically activated Macs at one extreme and M2 or alternatively activated Macs at the other extreme [4,5]. Human M2 Macs can be further classified as M2a, M2b and M2c (Fig. 1), the third being the most immunosuppressive Mac type. Recently, for in vitro differentiated macrophages, a nomenclature that clearly identifies the differentiation and activation stimuli used (e.g., M(IFN-γ), M(IL-4), M(IL-10), M(IFN-γ+LPS), etc.) has been proposed [1].