Mechanisms, Diagnosis and Treatment of Bone Metastases

Abstract

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients' quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.

Keywords: EMT; bone colonization; bone metastasis; bone reconstruction; metastasis targeted therapy; metastatic dormancy; metastatic niche; tumor microenvironment interactions.

Figure 1

Tumor–microenvironment interactions in bone metastasis. The bone metastatic process involves several steps, including epithelial-to-mesenchymal transition (EMT), colonization of the metastatic niche, tumor dormancy, immune evasion/osteomimicry, bone reconstruction and progression to overt metastases. At later stages, tumor cells secrete factors that stimulate osteoclasts or osteoblasts, leading to excessive bone loss (osteolysis) or bone formation (osteosclerosis), respectively. Most solid tumor metastases to bone exhibit a mixed phenotype of osteolytic and osteoblastic lesions. Highlighted are several key factors that are released by tumor cells and various cell types of the bone metastatic niche mutually controlling their metastasis-driving activities. Created with BioRender.com (accessed on 27 August 2021).

Figure 2

Bone metastasis-targeting drug candidates. Several therapeutic approaches exist to target different steps of the metastatic cascade. For example, the EMT process represents a possible therapeutic intervention point, and inhibitors against TGFBR1 and EGFR1 are currently being tested in clinical trials. Homing and colonization of the metastatic niche by disseminating cancer cells can be targeted using CXCR4 or E-selectin antagonists. Drug candidates targeting dormant tumor cells include AXL and TGFBR2 inhibitors. Bisphosphonates and the anti-RANK-L antibody denosumab can be used to inhibit osteoclast-mediated bone remodeling. Finally, several immunotherapeutic approaches to fight bone metastasis have been explored, including PD-L1 or CTLA-4 checkpoint inhibitors, CAR-T cell therapy and depletion of Tregs with anti-CD25 antibodies. Besides T cells, other immune cell types represent promising candidates for therapeutic targeting, including neutrophils, tumor-associated macrophages (TAMs), lymphoid cells, myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs). Created with BioRender.com (accessed on 27 August 2021).