br Discussion and outstanding questions

Discussion and outstanding questions Reproductive endocrine hormones such as inhibin affect breast cancer cell survival in the primary tumour and affect tumour homing and survival in the bone microenvironment. The molecular mechanism driving this effect of hormones in bone is likely to be multifactorial by modification of both paracrine factors and the cellular components of the bone metastatic niche. If the Ob niche is key to the maintenance of dormancy and survival of tumour cells then factors that affect the size of this niche can potentially determine outcomes for breast cancer cells in this environment. There is evidence from in vivo models that expanding the Ob niche with the use of parathyroid hormone, increased the number of DTCs in bone from sub-cutaneous prostate tumours [30]. Zoledronic hcv virus has also been shown to have effects on the Ob niche and a recent in vivo study evaluating the effects of a single dose of zoledronic acid (100μg/kg) showed that the drug significantly reduced Ob number which influenced where intracardiac injected MDA-MB-231 breast cancer cells home to, with a preference demonstrated for Ob rich areas [31]. Both inhibin and bisphosphonates differentially affect paracrine factors and cellular components of the bone metastatic niche, in particular the Ob niche, with potentially differential effects on the survival of DTCs in bone. The specific molecular mechanisms driving this need further elucidation to allow understanding and development of alternative bone targeted treatments that are mechanistically different to the osteoclast inhibitors and have anti-tumour efficacy in premenopausal women.
Introduction
Conclusion Bone metastasis depends on induction of proliferation and less on tumor cell seeding. The “seed and soil” theory of Paget implicates a balance between the influence of seeded tumor cells and of the microenvironment of the secondary organ. However, in bone tissue the microenvironment seems to be the main influential factor in facilitating bone metastasis. In prostate and breast cancer it is not the number of tumor cells seeded in bone tissue that affects the development of bone metastases but the growth supporting microenvironment of the bone, created by bone turnover [22]. The revival of dormant cancer cells in the bone tissue may also be influenced by changes in the bone microenvironment since in myeloma cells dormancy was shown to be switched off by osteoclasts remodeling [23]. However, an effect of calcium in this process could not be shown. Apart from other bone specific cytokines and growth factors, calcium is one of the key players in the formation of bone metastasis and should be taken into consideration when planning therapeutic strategies for preventing bone metastasis. In other diseases such as chronic obstructive pulmonary disease (COPD) or allergic asthma, calcilytics inhibiting CaSR are discussed as new therapeutics [24,25] and could also be used for preventing bone metastasis. Furthermore, the calcium mimetic Ra-223, blocking CaSR, is an example of a new bone-targeted therapy with potent antitumor effects in first trials [26].