br Introduction Bone marrow adipocytes are one
Introduction Bone marrow adipocytes are one of the most abundant cell types found in bone marrow tissue. They constitute approximately 15% of the bone marrow volume in young adults, rising to 60% by the age of 65 years old . Previously considered as inert space filling cells with little biological significance, accumulating evidence demonstrates that bone marrow adipocytes are more than just passive bystanders of the marrow. They have a distinctive phenotype, which resembles both brown and white adipose tissue and are now recognised to have specialised functions . They store and secrete fatty acids, cytokines and adipokines among them leptin and adiponectin, which regulate calorie intake and insulin sensitivity, respectively. Morphologically bone marrow adipocytes are smaller in size than their visceral counterparts; however the net effect of fatty EPZ 005687 uptake is similar due to enhanced triacylglycerol synthesis. They have the potential to influence neighbouring cells by autocrine, paracrine and endocrine signalling making them a powerful player in influencing the bone microenvironment as a whole. Marrow adipocytes and osteoblasts share common progenitor cells, known as bone marrow mesenchymal stromal cells (MSCs) . Their lineage commitment is thought to be regulated by adipogenic and osteogenic factors in the bone microenvironment that activate their respective transcriptional programs. However, in recent years the identification of MSC subpopulations that are thought to be lineage committed has added another level of complexity. The balance between these two cell types appears to play a pivotal role in bone homeostasis and so when the scales are tipped in favour of adipogenesis then by default osteoblastogenesis is negatively regulated. Moreover, there is a building body of evidence to suggest that a subpopulation of adipocytes are generated from bone marrow myeloid cells, posing the question as to how these differ in their function and behaviour to adipocytes generated from MSCs . Furthermore, bone marrow adiposity is also known to inhibit haematopoiesis . There is considerable evidence to support a metabolic role for marrow adipocytes however their influence on the development and progression of metastatic bone disease is only now becoming apparent.
Bone marrow adipocytes in the tumour-bone microenvironment The bone provides a unique and supportive microenvironment for a number of solid tumour metastases including breast, prostate and the haematological malignancy multiple myeloma . Cancer cells that intrude into this microenvironment produce various cytokines and growth factors which dysregulate the normal coupling of osteoclasts and osteoblasts. The increased bone resorption releases a number of factors which act positively upon the cancer cells thus perpetuating a “vicious cycle”, a feed-forward cycle that is critical to the establishment of bone metastasis. However, it would be short sighted to think that bone metastases only impinge upon osteoblasts and osteoclasts, as there are many more cells residing in the bone marrow such as fibroblasts, macrophages and adipocytes (Fig. 1) whose contribution should not be ignored. Bone metastatic cancers primarily occur in older patients whose bone marrow is heavily populated by adipocytes . In recent years there has been building interest in the contribution of marrow adipocytes to metastatic disease. In breast, multiple myeloma (MM) and prostate there is demonstrable evidence that marrow adipocytes attract and interact with cancer cells, however the advantages these interactions bestow are still open to debate. Diet-induced obesity has been shown to promote development of a myeloma-like condition, and to increase prostate cancer-induced bone disease [8–10]. Cancer cells are attracted to adipocytes within the metabolically active red marrow of the bone and these adipocytes interact closely with their neighbouring cells [9, 11–13]. These observations suggest that an adipocyte-rich environment could fuel disease by creating a permissive favourable niche for cancer cells to establish and progress.