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  • Both breast cancer and MM cause osteolytic lesions inhibitin


    Both breast cancer and MM cause osteolytic lesions, inhibiting osteoblast differentiation and thereby tipping the balance in favour of osteoclastic activity. In contrast, prostate cancer predominantly causes osteoblastic bone disease. Interestingly, increased marrow adiposity has been associated with both osteolytic and osteoblastic disease [8,10,14]. However, one crucial factor these two processes have in common is the need for energy. Adipocytes are filled with numerous lipid droplets which serve as an effective source of fatty acids when metabolic demand is increased. Podgorski and colleagues demonstrated that lipids can be trafficked between adipocytes and cancer p38 mapk inhibitor fuelling tumour growth and invasiveness by upregulating FABP4, IL-1β and HMOX-1 in the metastatic tumour cells [9]. Adipocytes also support cancer cells in an endocrine manner, secreting growth factors, adipokines and chemokines that lead to tumour survival. In MM factors such as IL-6, TNF-α, CXCL12 and leptin play a role in disease establishment and progression promoting cell proliferation and migration as well as preventing apoptosis [11,15]. In prostate cancer the chemokines CXCL1 and CXCL2 have been implicated in promoting tumour associated bone disease by upregulating osteoclastogenesis, and in turn promoting tumour cell survival [10]. Recently, breast cancer cells have been shown to be recruited to bone marrow adipose tissue by the secretion of IL-1β and leptin [16]. The abundance of marrow adipocytes in ageing bones may increase the fertility of the bone microenvironment by providing a constant source of energy and growth factors for cancer cells to thrive and progress in these skeletal sites. However, the identification of bone marrow adipocytes as a major source of circulating adiponectin [17], greater than white adipose tissue, raises the possibility that bone marrow adipocytes may also have anti-tumour functions due to the tumour-suppressive effects of adiponectin.
    Cancer-associated adipocytes Adipocytes located in close proximity to invasive cancer cells in the primary tumour exhibit profound phenotypic changes that include both morphological and functional alternations and are often referred to as cancer-associated adipocytes (CAAs). The morphological changes associated with these cells include loss of lipid content (delipidation) and acquisition of a fibroblast-like/preadipocyte phenotype (de-differentiation). Functionally they exhibit a decrease in expression of adipocyte-related genes such as adiponectin, FABP4 and resistin coupled with an increase in the production of pro-inflammatory cytokines IL-6, IL-1β [9,18]. These changes were primarily reported in breast cancer studies in associated with white adipose tissue, however recent in vitro work suggests these changes are also important in the bone marrow [9].
    Targeting adipocytes Given the potential tumour-supporting role of adipocytes, targeting these cells either alone or in combination with common therapeutics may be a promising approach. Modulating levels of adipokines such as adiponectin has been shown to exert an anti-tumour effect. Pharmacological enhancement of circulating adiponectin by the apolipoprotein mimetic L-4F was shown to cause cancer cell death in mouse models of myeloma [19]. Due to the increasing importance of lipid metabolism in tumour cell survival, drugs have been developed that target essential molecules of fatty acid synthesis and uptake. Chemical or RNAi-mediated inhibition of key enzymes involved in fatty acid synthesis, including fatty acid synthase (FASN) [20], acetyl-CoA-carboxylase and ATP-citrate lyase has been shown to attenuate tumour cell proliferation and induce cell death in a number of different cancer cell lines and mouse models [21]. Approaches that regulate the balance between adipogenesis and osteogenesis may also be effective in maintaining healthy bone homeostasis thereby preventing cancer infiltration. Modulation of the nuclear receptors, glucocorticoid receptor and PPARγ and their respective pharmacological ligands, corticosteroids and thiazolidinediones, directly regulate osteogenic versus adipogenic differentiation of MSCs [22] and so could be targeted accordingly. Another such target is protein kinase C which also promotes osteogenesis and has anti-tumourigenic properties [23]. Investigating these treatment strategies more closely may provide new insight in to which pathways are being exploited by cancer cells in order to evade conventional treatments. Targeting adipocytes as part of a combination therapy may prove to be a valuable tool, however a greater understanding between the balance of tumour-promoting and tumour-suppressive effects of bone marrow adipocytes is required.