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  • br Conclusions br Acknowledgements This work was supported b

    2019-06-21


    Conclusions
    Acknowledgements This work was supported by Bloodwise, the International Myeloma Foundation and a Marie Curie Career Integration Grant from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° [294160].
    The osteoblast in normal bone physiology Under normal physiological conditions osteoblasts are responsible for the formation of new bone in the developing skeleton and during the process of bone remodelling. Osteoblasts arise from the differentiation of mesenchymal parp apoptosis pathway committed to osteoprogenitors in the periosteum, via a process that requires sequential action of the transcription factors Runx2 and osterix [1]. These cells form closely packed sheets on the surface of bone from which they extend cellular processes through the developing bone. In order to successfully lay down new bone osteoblasts produce a range of molecules, including enzymes, growth factors and hormones such as, alkaline phosphatase, collagenase, TGF β, IGFs, osteocalcin and type 1 collagen [1]. After the process of bone formation, matrix synthesising osteoblasts have three potential fates: Some osteoblasts become flattened and remain as quiescent lining cells at the bone surface and some die by apoptosis. However, with the deposition of new bone, the majority of osteoblasts gradually become surrounded by the bone matrix and as the matrix calcifies the cells (along with their associated cell products) gets trapped inside the resulting lacunae. At this point cells of the osteoblast lineage further differentiate into osteocytes [2,3]. Osteocytes communicate with each other as well as with osteoblasts, via extensive cytoplasmic processes that occupy canaliculi within the bone matrix. Both bone lining cells and osteocytes have been identified as important sources of RANKL [4]. Thus, interactions between RANKL from osteoblasts/osteocytes and RANK on osteoclasts directly affect osteoclastogenesis, regulating osteoclastic bone resorption and the release of growth factors from the bone matrix.
    Tumour cell homing and colonisation of bone Bone is the third most common site for tumour cells to spread and bone metastasis affects more than 600, 000 people every year in the USA alone [5]. The site at which secondary tumours form is not random; for metastases to parp apoptosis pathway develop tumour cells must arrive in an environment that is permissive for their colonisation and subsequent growth. In the case of bone metastasis it is hypothesised that tumour cells home to specific niches: The endosteal niche (which is primarily made up of osteoblasts), the haematopoietic stem cell (HSC) niche and the vascular niche (reviewed by Maggague and Obenauf, 2016 and Weilbaecher, et al. 2011 [6–7]). Evidence from in vivo models suggest that all of these niches play a role in tumour cell metastasis to bone and that interplay between these niches determines whether tumour cells proliferate to overt metastases or remain dormant.
    Progression to overt metastases When established in bone, cancer cells influence bone cells in two predominant ways. Most often cancer cells stimulate the osteoclast lineage to increase osteoclast differentiation and activity whilst simultaneously inhibiting osteoblasts [2]. When this happens, osteoclastic bone resorption exceeds osteoblastic bone formation resulting in bone degradation and the formation of osteolytic lesions (common in breast, lung and multiple myeloma). In some cases, instead of inhibiting osteoblasts, cancer cells release substances to stimulate the osteoblast lineage to increase osteoblast differentiation and new bone deposition. When osteoblastic bone formation exceeds osteoclastic bone resorption increased bone growth results in \'bulges’ in the mineralised tissue where tumour cells reside causing osteoblastic lesions. Because osteoblastic bone metastases is characterised by increases in both bone resorption and bone formation lesions consist of weakened bone with abnormal architecture and patients with this condition are at increased risk of fracture (common in prostate) [16]. Although more patients present with osteolytic lesions than osteoblastic the distinction between the two-types is not absolute and many patients with bone metastasis have both osteolytic and osteoblastic lesions [17]. Mechanistically, osteoclasts and osteoblasts play significant roles in the formation of both lesion types, however, this article primarily focuses on osteoblasts. Evidence is emerging for a direct role of osteoblasts on tumour growth in bone. In a mouse model of breast cancer metastasis to bone, increasing the osteoblastic niche with PTH before intra-cardiac injection of human breast cancer cells caused an increase in numbers of overt bone metastases without altering tumour cell dissemination in bone [18]. Pro-tumourigenic effects of PTH have also been observed in rats treated with high doses of PTH [2]. However, in mouse models of multiple myeloma, daily injection with PTH suppressed tumour growth whilst increasing bone formation [19]. The effects of PTH on tumour growth in bone, however, may not be solely due to changes in osteoblasts. PTH treatment has profound affects upon the bone microenvironment that go beyond increased osteoblast numbers and activity. In all of the above studies PTH affected osteoclasts and it is likely that the gross morphological changes that occur in bone, following this treatment, are accompanied by alterations to the vascular niche, although this hypothesis remains to be explored. It has been suggested that osteoblasts and multiple myeloma cells have inhibitory effects upon each other and in their review Suvannasankha and Chirgwin hypothesise that these inhibitory effects may also occur between breast cancer cells and osteoblasts [2]. The effects of osteoblasts on tumour growth and progression to metastasis, therefore, warrants further investigation.