Cell differentiation-related signaling pathways in hepatocellular carcinoma metastasis

Primary liver cancer is the third leading cause of cancer-related deaths worldwide, with persistently high incidence and mortality rates. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has a complex pathogenesis. Moreover, due to the low rate of early diagnosis and limited treatment options, the prognosis for HCC patients is poor, with a median overall survival of approximately one year for advanced-stage HCC. Cancer metastasis is one of the main reasons for HCC-related deaths. During the metastatic process, tumor cells undergo a series of complex biological changes, including epithelial-mesenchymal transition, extracellular matrix remodeling, angiogenesis, and resistance to anoikis, which are key steps. These changes promote the invasion and migration of tumor cells and are central mechanisms of cancer progression. In the metastatic process of HCC, signaling pathways that regulate cell proliferation, differentiation, and apoptosis, such as Hippo-YAP/TAZ, Wnt/β-catenin, Notch, Hedgehog and JAK/STAT, become dysregulated and play a promoting role in the aggressive growth and distant migration of HCC cells. Treatment strategies targeting these pathways are currently being developed. These new agents, being more targeted, may have better tolerability and fewer adverse effects. This review focuses on the role of these key signaling pathways in the metastatic process of HCC and summarizes the treatment strategies targeting these pathways.