Bone Marrow Adipose Tissue: A New Player in Cancer Metastasis to Bone

Abstract

The bone marrow is a favored site for a number of cancers, including the hematological malignancy multiple myeloma, and metastasis of breast and prostate cancer. This specialized microenvironment is highly supportive, not only for tumor growth and survival but also for the development of an associated destructive cancer-induced bone disease. The interactions between tumor cells, osteoclasts and osteoblasts are well documented. By contrast, despite occupying a significant proportion of the bone marrow, the importance of bone marrow adipose tissue is only just emerging. The ability of bone marrow adipocytes to regulate skeletal biology and hematopoiesis, combined with their metabolic activity, endocrine functions, and proximity to tumor cells means that they are ideally placed to impact both tumor growth and bone disease. This review discusses the recent advances in our understanding of how marrow adipose tissue contributes to bone metastasis and cancer-induced bone disease.

Keywords: bone metastasis; cancer-induced bone disease; marrow adipose tissue; multiple myeloma; prostate cancer.

Figure 1

An overview of the potential contribution of both white adipose tissue (WAT) and bone marrow adipocytes (BMAs) to the vicious cycle of bone metastases. Dysfunctional WAT releases an increased level of a number of adipokines and pro-inflammatory cytokines that can support tumor growth. In turn, cancer cells may cause delipidation of adipocytes to fuel their growth and the acquisition of an aggressive metastatic phenotype. They can then metastasize to the adipocyte-rich environment of the bone where they may continue to utilize BMAs generated from mesenchymal stem cells (MSC) that reside in the bone, as a source of fuel. Cancer cells residing in the bone produce various cytokines and growth factors that primarily target osteoblasts, causing them to increase their production of receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL in turn targets the RANK receptor expressed by osteoclast precursors and leads to differentiated and activated osteoclasts. The osteoclasts degrade the bone releasing numerous factors. Many of these factors act positively upon the cancer cells resulting in a vicious cycle.