Bone Metastasis: Find Your Niche and Fit in

Abstract

Metastasis to bones is determined by both intrinsic traits of metastatic tumor cells and properties appertaining to the bone microenvironment. Bone marrow niches are critical for all major steps of metastasis, including the seeding of disseminated tumor cells (DTCs) to bone, the survival of DTCs and microscopic metastases under dormancy, and the eventual outgrowth of overt metastases. In this review, we discuss the role of bone marrow niches in bone colonization. The emphasis is on complicated and dynamic nature of cancer cells-niche interaction, which may underpin the long-standing mystery of metastasis dormancy, and represent a therapeutic target for elimination of minimal residue diseases and prevention of life-taking, overt metastases.

Keywords: bone marrow niches; bone metastasis; disseminated tumor cells; hematopoietic stem cells.

Figure 1. Steps of Bone Metastasis

Bone metastasis is a multiple-step and lengthy process. Facilitated by EMT and the primary tumor microenvironment (eg. hypoxia and cancer associated fibroblasts), invasive tumor cells may intravasate into the blood vessel as single circulating tumor cells (CTCs) or CTC clusters. While in circulation, CTCs may aggregate with platelets to survive against physiochemical pressure and immunosurveillance. After arrival at the bone marrow vasculature, CTCs attach and adhere to the bone marrow endothelium via intercellular adhesion, and extravasate into bone marrow parenchyma. T umor cells may subsequently enter a dormant state for a prolonged period of time, until they are re-activated under favorable conditions to form micrometastasis. The progression of micrometastases into overt metastases is limited by neo-angiogenesis and immunosurveillance mechanisms. Overt metastases in bone commonly leads to abnormal bone growth or resorption, both of which reduce bone strength and increase the risk of bone fracture.

Figure 2. Mechanism of Osteoblastic and Osteolytic Metastasis

Both osteoblastic and osteolytic metastasis involve the interactions between tumor cells, osteoblasts, and osteoclasts. Tumor cells directly and indirectly alter the balance between RANK ligand (RANKL) and its antagonist osteoprotegerin (OPG), which has profound effects on bone homeostasis. In osteoblastic lesions, tumor cells secrete cytokines to promote osteoprogenitor cell recruitment and differentiation, as well as osteoblast proliferation. The activated osteoblasts may create a tumor favorable environment by producing bone matrix proteins and growth factors. Due to the coupling of osteoblast and osteoclast activities, osteoclasts are also stimulated in osteoblastic lesions. However, the overall bone resorption rate is lower than that of bone formation, possibly due to a relatively low ratio of RANKL to OPG in the environment. Thus, the net effect on bone is an abnormal increase in bone mass. On the other hand, osteolytic tumor cells secrete osteolytic factors such as PTHrP and IL-11, which induces osteoblast production of RANKL, therefore promoting osteoclastogenesis. Osteolytic tumor cells can also directly activate osteoclasts through expressing RANKL, Jagged1, and metalloproteinases. Increased osteoclastic activity leads to bone destruction, and releases growth factors and calcium from the bone matrix, which in turn support the expansion of tumor cells. In multiple myeloma, tumor secretions can also inhibit the differentiation of osteoprogenitor cells and contribute to the reduced bone formation.

Figure 3,. Key Figure Bone Marrow Niches for Metastatic Tumor Cells

Generally, two different bone marrow niches may host tumor cells. Osteogenic niches (or endosteal niches) are adjacent to the endosteum, which are comprised mainly of osteoblastic cells. Our work suggested that osteogenic cells establish physical connection with residing tumor cells through heterotypic adheren junctions and gap junctions. This interaction activates the mTOR pathway in cancer cells and triggers calcium influx from niche cells, which promotes cancer cell survival and proliferation. By contrast, the perivascular niche is proposed to be a dormancy permissive niche. TSP-1 from endothelial cells maintains tumor cells in a dormant status. Other stromal cells in the perivascular niche are highly heterogenous, including MSCs expressing NG2+, Nes-GFP+, LepR+, or CXCL12 abundant reticular cells (CAR). As such, the perivascular niches may exert complex effects on residing tumor cells. Given that the endosteum is also highly vascularized, it is plausible that osteogenic niches and perivascular niches may spatially overlap in the endosteal region. In addition, MSCs can undergo osteogenic differentiation to generate osteoblastic lineage in vivo. Other cells types found in the bone marrow, including lymphocytes, MDSCs, macrophages, adipocytes, osteoclasts, megakaryocytes, and sympathetic nerves, can directly and indirectly participate in these two niches to orchestrate the progression of bone metastasis.