br Future directions There is increasing evidence

Future directions There is increasing evidence that osteoblasts are important components of the bone metastatic niche, but their precise contribution in supporting tumour cell engraftment, dormancy and survival remains to be defined. Unlike osteoclasts, the role of osteoblasts in bone metastasis is relatively under-investigated. Increased understanding of how this cell type interacts with tumour cells in the bone environment may be essential, if we are to identify better therapeutic strategies for treating patients with this condition. The potential importance of osteoblasts in therapies has already been acknowledged with novel treatments aimed at targeting bone formation already being put into clinical practise. Traditional drugs such as bisphosphonates were developed to target osteoclasts; however, these drugs also inhibit osteoblasts [8,25]. Initial, laboratory testing indicated that targeting RANKL may be more selective, reducing osteoclasts whilst increasing bone formation, via increased differentiation of osteoblasts (reviewed by Sims and Romas, 2015 [26]). However, when used in clinic, the human RANKL inhibitor, denosumab inhibited serum bone resorption and formation markers in women with osteoporosis [27]. It therefore seems likely that the close coupling of osteoclasts/osteoblasts will make it impossible to use a single drug or a combination of drugs at the same time point, to both resorb and repair bone. It is also likely that osteoclast targeted therapies designed to prevent progression of osteolytic lesions in bone are also responsible for impaired healing and weakened bones seen in myeloma patients after administration of these treatments [28]. It is therefore proposed that a useful strategy to reverse bone loss would be to turn on osteoblast functions. Evidence from patients with multiple myeloma and lymphomas has demonstrated that the proteasome inhibitors bortezomib and carfilzomib both promote bone formation by stimulating progenitor proliferation and osteoblast differentiation. This drug is now FDA approved for patients with multiple myeloma and mantle cell lymphoma [2,29–30]. Furthermore, proteasome inhibitors have also been shown to prevent osteolytic lesion formation in pre-clinical models of breast cancer bone metastasis [31]. These data indicate that targeting osteoblasts in combination with osteoclast inhibition may provide promising bone sparing agents for patients with bone metastases [32]. However, it must also be noted that many drugs that have bone anabolic effects including the proteasome inhibitors bortezomib, carfilzomib as well as ZSTK474 that neutralise the WNT inhibitors DKK1 and Sclerostin also have direct anti-tumour effects. It is, therefore, impossible to deduce whether these compounds are exerting bone sparing effects or whether decreased loss of bone is a side effect of reduced tumour burden [2,30].
Unanswered questions
Introduction Metastatic dissemination of cancer cells to local and distant sites such as bone requires a complex interaction of cancer cells with their surrounding microenvironment to allow invasion, immune evasion and spread via the vascular or lymphatic systems. The tumour microenvironment is composed of an array of cells embedded in a complex extracellular matrix (ECM) (Fig. 1). The predominant cell type of the tumour microenvironment, the fibroblast, becomes corrupted by cues derived from malignant cells and other cells present in the tumour stroma to become cancer-associated fibroblasts (CAF). The presence of CAF correlates with poor disease outcome in a number of tumours, leading to the suggestion that they may present a viable novel therapeutic target. In this review we summarise the roles of CAF in the metastatic cascade and focus on the emerging understanding of their contribution to dissemination and growth of tumours in bone.
Cancer associated fibroblasts – bad neighbours in the tumour microenvironment Malignant tumours grow and spread by corrupting the surrounding stroma, composed of cells such as fibroblasts, endothelial cells, and immune cells (Fig. 1), to encourage cancer cells to proliferate, evade the host’s immune system, and metastasise. There exists considerable evidence highlighting the prognostic importance of various components of the modified cancer microenvironment, including cancer-associated fibroblasts (CAF) [1–3]. CAF are the most abundant cell type in the tumour microenvironment but reliably identifying them remains challenging due to their heterogeneity [4]. CAF express mesenchyme specific markers such as fibroblast activating protein (FAP), fibroblast specific protein 1 (FSP1/S100A4), vimentin, platelet derived growth factor receptors, podoplanin and the most commonly used marker, alpha smooth muscle actin (α-SMA) [5], but many of the markers used to identify them are expressed by other cell types; for example podoplanin is found in lymphatic vessels, as well as some cancer cells or, platelet-derived growth factor receptor β (PDGFRβ) is expressed by pericytes . Some of the heterogeneity observed in CAF populations may result from subpopulations arising from different origins; resident fibroblasts, mesenchymal stem cells, fibrocytes, stellate cells (pancreas, liver), Kuppfer cells (liver), endothelial cells, smooth muscle cells, myoepithelial cells (breast), pericryptal myofibroblasts (gastrointestinal tract) have all been demonstrated to give rise to CAF [6,7]. It is notable, however, that the heterogeneity of CAF is generally accepted to arise not from genomic changes (ie alterations in DNA sequence) but rather from epigenetic and other modifications of gene expression. This is significant as the genomic stability of CAF make them less likely to acquire resistance to therapy frequently encountered when pharmacologically targeting genomically unstable cancer cells, and therefore an attractive target for intervention [4].