Bone metastasis: mechanisms, therapies, and biomarkers

Abstract

Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability), which negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process; long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis

“…Understanding osteoclast signaling in bone metastasis could help to identify new targets for drug discovery [ 153 ], and there are currently drug candidates in different phases of development that are targeting osteoclasts, such as SRC, DKK-1, and Sclerostin-targeting compounds [ 154 ]. Additionally, importantly, interactions with other cell types in the bone metastatic microenvironment could potentially provide new treatment options for bone metastases [ 155 ].…”

IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer

“…The role of the immune system in controlling metastatic tumour cell dormancy in bone remains to be explored 8 . As current treatments for metastatic breast cancer are predominantly palliative, there is an urgent clinical need to identify new biomarkers of metastatic BC and to develop more effective therapies 9 .…”

Fracture Risk Evaluation of Bone Metastases: A Burning Issue

“…Bone dissemination occurs early during cancer progression and follows a complex multistep process, involving specific cellular properties of some cancer cell sub-populations of the primary tumor, such as loss of cell-cell interactions, epithelial-to-mesenchymal transition, migration/invasion, and dissemination through circulation [1][2][3][4][5]. These properties are required for cancer cells to colonize a distant organ, settle in this new environment, and create a metastatic niche.…”

“…Once in the bone marrow niche, these cells, known as disseminated tumor cells (DTC), may remain quiescent, sometimes for years or decades, before they become clinically detectable [6]. This period of latency is known as tumor dormancy and involves a dynamic interplay between cancer cells and cells from the bone marrow microenvironment, such as spindleshaped N-cadherin+/CD45-osteoblast (SNO) cells, CXCL-12-abundant reticular (CAR) cells, stromal cells, mesenchymal stem cells, and immune cells [4,[7][8][9]. Changes in the bone environment in favor of osteoclast-mediated bone resorption are sufficient to trigger dormant cell reactivation, which is why bone-targeted agents, such as bisphosphonates, by decreasing bone resorption, improve the elimination of DTCs in the bone marrow of breast cancer patients with a minimal residual disease [4,10].…”

“…This period of latency is known as tumor dormancy and involves a dynamic interplay between cancer cells and cells from the bone marrow microenvironment, such as spindleshaped N-cadherin+/CD45-osteoblast (SNO) cells, CXCL-12-abundant reticular (CAR) cells, stromal cells, mesenchymal stem cells, and immune cells [4,[7][8][9]. Changes in the bone environment in favor of osteoclast-mediated bone resorption are sufficient to trigger dormant cell reactivation, which is why bone-targeted agents, such as bisphosphonates, by decreasing bone resorption, improve the elimination of DTCs in the bone marrow of breast cancer patients with a minimal residual disease [4,10]. Additional signals are likely to be involved in tumor cell reactivation, and the identification of these molecular players is under intense investigation as they might represent an opportunity for therapeutic targeting.…”