Review of the premetastatic niche in liver cancer bone metastases

Liver cancer bone metastasis, a severe complication of liver cancer, is a leading cause of cancer death in China, featuring poor prognosis, intractable pain, and impaired quality of life. At present, the research of liver tumor bone metastasis mostly focuses on the treatment means and biological behavior analysis of malignant liver cancer, but the construction of the microenvironment before liver tumor metastasis is rarely studied. Unpredictable tumor metastasis hinders early intervention, leading to low cure rates. Since proposed the "premetastatic niche" concept was proposed in 2009, it has offered a novel framework for explaining liver cancer bone metastasis, supplementing traditional theories (e.g., "soil theory", "seed theory") and becoming a research focus. Herein, we review the premetastatic niche theory's origin, induction factors, mechanisms, and advances in liver cancer bone metastasis. Premetastatic niche formation is mainly induced by two factors: primary tumor-derived soluble factors (TDSFs) and extracellular vesicles (EVs). TDSFs (e.g., LOX, G-CSF, CCL2) are secreted under hypoxia and inflammation, reaching target organs via blood to promote matrix remodeling, recruit BMDCs, and establish immunosuppression. EVs carry mRNA, microRNA, and integrins, modifying target cell biology to facilitate PMN formation (e.g., Src phosphorylation, proinflammatory factor upregulation). BMDCs - especially MDSCs, neutrophils, and macrophages - are core PMN components. They interact with resident cells (e.g., hepatic stellate cells, osteoblasts) to secrete growth factors and matrix proteins, remodeling the microenvironment for tumor colonization. Animal studies confirm key regulatory molecules: TIMP-1 induces liver niches via SDF-1 upregulation and Ly6G+ neutrophil recruitment; CXCR2 inhibition reduces metastasis by limiting BMDCs and boosting immunity. While premetastatic niche research in liver cancer bone metastasis remains preliminary, it holds promise for clinical prevention and diagnosis. Future studies should clarify its molecular mechanisms and validate findings in clinical samples, laying the groundwork for translating this theory to improve patient prognosis.