br Macrophages br Bone metastasis Bone metastasis is

Macrophages
Bone metastasis Bone metastasis is a multi-step process that takes place in the later stages of tumour progression. Initial steps, all involving macrophages, include the detachment of tumour daunorubicin from the primary tumour and their invasion into the circulation. Once in the circulation, tumour cells move towards the preferred target tissues, such as bone, where they adhere to the endosteal surface and form small tumour colonies [45]. The exact mechanism driving the tumour cells to metastasise to bone remains to be identified, but the various cell types (including macrophages), extracellular matrix components and soluble factors present in the bone microenvironment provide the ideal site for tumour cell colonisation and survival [46]. During the development of cancer-induced bone disease, a range of growth factors that enhance tumour cell proliferation are secreted and activated, including insulin-like growth factors (IGF) I and II, transforming growth factor β (TGFβ), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), calcium and bone morphogenic proteins (BPMs) [47]. Cancer cells in turn release factors that that stimulate bone remodelling, therefore promoting the development of osteoblastic or osteolytic metastases [48].
Summary and conclusions Studies using both murine models and human tumours have provided unequivocal evidence for a role of TAMs in tumour progression, and potentially in promotion of tumour metastasis, through regulation of adaptive immunity, stroma remodelling, basement membrane breakdown and angiogenesis. Although direct evidence of a specific role for macrophages in bone metastasis remains limited, there is accumulating evidence from in vivo models supporting their involvement. However, it remains to be determined which stages of the process macrophages contribute to, in particular their role in early colonisation of bone compared to the latter stages associated with cancer-induced bone disease. A major complication encountered in the studies that have aimed to determine the role of macrophages in bone metastasis is that the various tools and methods used to modify the number of macrophages also affect osteoclasts, due to the similarity in molecular profile and phagocytic capacity between these closely related cell types. As the osteoclast is established as a key driver of tumour growth and progression in bone, it has therefore been impossible to clearly distinguish between the consequences of macrophage depletion and those mediated by inhibition of bone resorption. Macrophages in bone metastasis – main outstanding questions:
Conflict of interest statement
Acknowledgements IV was supported by a generous grant from Weston Park Hospital Cancer Charity, Sheffield, UK.
Introduction In recent years there has been increasing interest in the role of bone-targeted agents, such as bisphosphonates (BP) and denosumab, as adjuvant therapies for breast cancer. The results of large randomized trials with BPs have been variable showing either; benefit [1–3], no benefit [4–7] or harm [8]. However, subgroup analyses have consistently shown that, where benefit exists, it is in women with a “low estrogen environment” either through menopause or suppression of ovarian function. In this manuscript, we review the link between estrogen and breast cancer risk and the hypothesis that estrogen levels may in part explain the response of patients to bone-targeted agents in the adjuvant setting.
Estrogen and breast cancer link The pivotal role of cyclical estrogens in breast cancer risk is well recognized. This has been shown in epidemiological studies where risk is related to earlier age at menarche, later age at first birth and menopause, and parity [9,10]. Breastfeeding is protective and is theorized to be secondary to increased prolactin secretion and subsequent suppression of estrogen production [11–13]. Studies on hormone replacement therapy (HRT) have shown increased risk of breast cancer while receiving combined estrogen and progesterone hormone replacement [14,15] and, interestingly, a fall in risk on discontinuation [15–17]. Obesity has also been shown to increase breast cancer risk in postmenopausal women, which is likely due to adipose tissue facilitating the conversion of adrenally secreted dehydroepiandrosterone (DHEA) into estrogen, leading to elevated estrogen levels [18]. In addition, several studies note that higher serum levels of estrogen in postmenopausal women are associated with increased breast cancer risk [19–23]. A meta-analysis of nine prospective studies, with data on 2428 predominantly postmenopausal women, 663 with breast cancer, demonstrated a roughly twofold higher risk of breast cancer in women with higher serum estrogen (2nd–4th quartiles) compared to those with lower levels (1st quartile) [24].
Estrogen and bone