Bone marrow niches in the regulation of bone metastasis

Abstract

The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune response are precisely regulated. These different cellular components constitute specialised tissue microenvironments-niches-that play critical roles in controlling tumour cell colonisation, including initial seeding, dormancy and outgrowth. In this review, we will dissect the dynamic nature of the interactions between tumour cells and bone niches. By targeting certain steps of tumour progression and crosstalk with the bone niches, the development of potential therapeutic approaches for the clinical treatment of bone metastasis might be feasible.

Fig. 1. The normal bone marrow niche.

Normal bone tissue contains two major bone marrow niches that support haematopoiesis and osteogenesis—the endosteal niche and the perivascular niche.

Fig. 2. The perivascular and endosteal niches in bone metastasis.

Tumour cells interact with different niche cells for metastatic colonisation in bone. a In the perivascular niche, similar to HSCs, tumour cells interact with bone-marrow stromal cells (BMSCs), which express the chemokine ligand CXCL12. Endothelial E-selectin engages in tumour cell to promote mesenchymal-to-epithelial transition, stemness, survival, and growth. b In the endosteal niche, tumour cells are thought to alter the normal balance of bone turnover by directly activating osteoclast formation by expressing the Notch ligand Jagged1 or vascular cell adhesion molecule (VCAM)1 or by inducing osteogenic cells (stromal cells, lining cells, osteoblasts and osteocytes) to produce the osteoclast-stimulating factors macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κΒ ligand (RANKL). Osteoclast-mediated bone resorption leads to the release of transforming growth factor (TGF)-β, which facilitates a ‘vicious cycle’ to fuel the development of osteolytic bone metastasis. Osteoblasts also promote bone metastasis by secreting Wnta5a and interleukin (IL)-6 or forming gap junctions and E-cadherin/N-cadherin junctions.

Fig. 3. Other cells in the bone metastatic niche.

Other cells in the bone niches include immune cells in the bone marrow (dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, T cells and megakaryocytes), adipocytes and sympathetic nerve cells. These bone stromal cells regulate the immune escape, dormancy and proliferation abilities of tumour cells.