Neurotrophic signaling in liver cancers: mechanisms and potential therapeutic targets

Recent studies demonstrate that peripheral innervation and Schwann cells (SCs) activity within the tumor microenvironment (TME) have a significant influence on liver cancer, specifically hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Even though the role of SCs in HCC behavior is only hypothetical, neurotrophic factors like brain-derived neurotrophic factor (BDNF) and artemin (ARTN) enhance tumor growth, angiogenesis, and metastasis. Thus, targeting these pathways has a promising therapeutic potential. Conversely, receptors such as glial cell line-derived neurotrophic factor family receptor α-1 (GFRα1) and factors like neurotrophin-3 (NTF3) exhibit tumor-suppressive roles, indicating a context-dependent, dual impact of neurotrophic signaling in liver cancer. In iCCA, perineural invasion (PNI) correlates with poor prognosis, with SCs promoting tumor progression through the secretion of neurotrophic factors such as nerve growth factor (NGF) and BDNF, which activate signaling pathways downstream. These pathways facilitate epithelial-mesenchymal transition (EMT), invasion, and neural infiltration. This review emphasizes the complex roles of neurotrophic factors in hepatic tumors and their future potential as biomarkers and therapeutic targets via disruption of tumor-nerve interactions.