Bone Marrow Adipocyte: An Intimate Partner With Tumor Cells in Bone Metastasis

Abstract

The high incidences of bone metastasis in patients with breast cancer, prostate cancer and lung cancer still remains a puzzling issue. The "seeds and soil" hypothesis suggested that bone marrow (soil) may provide a favorable "niche" for tumor cells (seed). When seeking for effective ways to prevent and treat tumor bone metastasis, most researchers focus on tumor cells (seed) but not the bone marrow microenvironment (soil). In reality, only a fraction of circulating tumor cells (CTCs) could survive and colonize in bone. Thus, the bone marrow microenvironment could ultimately determine the fate of tumor cells that have migrated to bone. Bone marrow adipocytes (BMAs) are abundant in the bone marrow microenvironment. Mounting evidence suggests that BMAs may play a dominant role in bone metastasis. BMAs could directly provide energy for tumor cells, enhance the tumor cell proliferation, and resistance to chemotherapy and radiotherapy. BMAs are also known for releasing some inflammatory factors and adipocytokines to promote or inhibit bone metastasis. In this review, we made a comprehensive summary for the interaction between BMAs and bone metastasis. More importantly, we discussed the potentially promising methods for the prevention and treatment of bone metastasis. Genetic disruption and pharmaceutical inhibition may be effective in inhibiting the formation and pro-tumor functions of BMAs.

Keywords: adiponectin; adipose; bone marrow adipocyte; bone metastasis; interleukin-6; leptin; tumor necrosis factor-α.

Figure 1

BMAs provide energy for tumor cells. De novo fatty acid synthesis is performed via glycolysis and glutaminolysis in tumor cells. The rate-limiting enzyme ACC is indispensable in the lipid droplet formation in tumor cells. Exogenous FFA could derived from BMAs. Tumor cells secrete some factors to promote the adipogenic differentiation of LepR⁺/Sca1⁺BMSCs in the early stage, as the tumor proliferate rapidly, large amount of tumor cells promote mature BMAs to de-differentiate into fatless fibroblast in the later stage. Lipid-breakdown factors from tumor cells enhance the lipolysis of mature adipocytes. The initial step of triglyceride hydrolysis is predominantly performed by ATGL and triglyceride is broken up to diacylglycerol. Then diacylglycerol is hydrolyzed into monoglyceride. FFA is transported by fatty acid binding protein 4 (FABP4). Tumor cells could also express FABP4 that could transfer free fatty acid when they are co-cultured with BMAs. Tumor cells transport FFA from cytosol into mitochondria for fatty acid oxidation (FAO) and produce ATP. This process is mainly performed by carnitine palmitoyltransferase-1 (CPT1A).

Figure 2

BMAs enhance tumor cell proliferation and resistance to chemotherapy and radiotherapy. Chemotherapy and radiotherapy enhance the rapid expansion of BMAs in tumor patients, followed by enhanced intracellular calcium ions in tumor cells and increasing FFA released from BMAs. On one hand, FFA is transported into tumor cells by CD36 and then FFA is transported to the nucleus by FABP4. FFA binds to the essential ligands of nuclear receptor PPARγ, followed by enhanced expression of CD36, FABP4, Pim2 and Bcl2, as well as the autophagy marker LC3-II. On the other hand, BMAs induce the autophosphorylation of SIK2, which then inhibits ACC and activates PI3K/AKT signaling. Increasing FFA from BMAs is transported into mitochondria and produces ATP in the energy deficiency condition. In this way, ROS is reduced and tumor cells survival in the bone marrow niche is enhanced.