A summary of neurotrophic factor-mediated biological effects in HCC and iCCA.
| Cancer | Neurotrophic factor | Biological outcomes | References |
|---|---|---|---|
| HCC | BDNF | BDNF promotes HCC progression by activating PI3K/AKT and Wnt signaling, enhancing proliferation, angiogenesis, and resistance to apoptosis. Lupeol suppresses BDNF secretion and reactivates GSK-3β, reducing tumor cell survival. Clinically, high BDNF/TrkB expression correlates with advanced stage, multifocality, and poor prognosis; its inhibition induces apoptosis and limits invasion. | [13–15] |
| ARTN | ARTN is upregulated by hypoxia via HIF-1α and promotes HCC progression through AKT-mediated EMT, stemness, and survival. Its overexpression enhances proliferation, invasion, and tumor-initiating capacity, and correlates with larger tumors, higher recurrence, and poor prognosis. | [16] | |
| INDO5 | INDO5, a dual Trk/c-Met inhibitor, suppresses HCC cell growth by reducing AKT and ERK signaling and activating apoptosis via caspase-3 and PARP cleavage. In vivo, it decreases tumor size and proliferation, with enhanced efficacy when combined with sorafenib, highlighting its therapeutic potential in targeting neurotrophic signaling in HCC. | [17] | |
| GFRα1-GDNF | GFRα1 acts as a tumor suppressor in HCC; its downregulation promotes proliferation via Wnt/β-catenin activation, while its expression enables GDNF-mediated growth inhibition. Low GFRα1 levels correlate with poor prognosis and increased sensitivity to oxaliplatin, suggesting its dual role as a prognostic and predictive marker. | [18] | |
| NTF3 | NTF3 is downregulated in HCC and correlates with poor prognosis; functionally, it acts as a tumor suppressor by promoting apoptosis and limiting tumor progression via JNK and p38 MAPK activation. Its expression is regulated by the c-Jun transcriptional factor and may serve as both a prognostic marker and therapeutic target. | [19, 20] | |
| iCCA | NGF | SCs-derived NGF promotes iCCA progression by enhancing tumor cell proliferation, migration, invasion, and PNI. These effects are mediated via TrkA signaling and are associated with EMT induction. Furthermore, high NGF/TrkA expression predicts poor prognosis and enhances proliferation and invasion via MAPK and PI3K/AKT signaling pathways. | [25, 26] |
| BDNF | BDNF expression in iCCA correlates with PNI and poor prognosis; functionally, it promotes tumor cell invasion in an autocrine/paracrine manner. | [27] | |
| LINC01812 | iCCA-derived exosomal lncRNA LINC01812 induces M2 macrophage polarization via TUBB4B/Notch/CCL2 signaling and increases the secretion of NGF and BDNF, which promote iCCA cell migration toward nerves and enhance PNI both in vitro and in vivo. | [28] |
ARTN: artemin; BDNF: brain-derived neurotrophic factor; GDNF: glial cell line-derived neurotrophic factor; HCC: hepatocellular carcinoma; iCCA: intrahepatic cholangiocarcinoma; NGF: nerve growth factor; NTF3: neurotrophin-3; EMT: epithelial-mesenchymal transition; lncRNA: long non-coding RNA; PNI: perineural invasion; TrkA: tropomyosin receptor kinase A; TrkB: tropomyosin receptor kinase B; GFRα1: GDNF family receptor α-1; TUBB4B: tubulin beta-4B chain; SCs: Schwann cells.