Liver Cancer Bone Metastasis: Molecular Mechanisms and Therapeutic Insights.

Liver cancer is a highly aggressive malignancy, and bone metastasis is a severe complication that negatively affects prognosis and quality of life. However, the molecular mechanisms underlying liver cancer bone metastasis remain poorly understood. This review examined recent advances related to epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs), and liver cancer stem cells (LCSCs), with a focus on surface markers, interactions within bone marrow (BM) niche, and relevant signaling pathways. Liver cancer bone metastasis is driven by EMT activation, CTC dissemination, and LCSC colonization in BM niches. Surface markers such as CD133, CD44, CD90, CD13, EpCAM, and OV6 contribute to tumor heterogeneity, dormancy, and therapy resistance. Key processes such as BM homing, osteolysis, and immune suppression are regulated through the osteoblast-osteoclast-cancer stem cell (OB-OC-CSC) axis and CXCL12-CXCR4 signaling. Dormancy-regulating molecules, including Annexin II, GAS6, osteopontin, TSP-1, tenascin C, and fibronectin, further determine CSCs' quiescence or reactivation. These insights highlighted the complexity of liver cancer bone metastasis, and suggested potential therapeutic strategies targeting EMT, LCSCs, and OB-OC-CSC crosstalk. Future studies are encouraged to validate marker functions in clinical cohorts, elucidate dormancy-exit mechanisms, and explore immunomodulatory interventions to overcome microenvironment-mediated resistance.