Ntn4, also known as Netrin-4, is a member of the neurite guidance factor family. It can promote neurite growth and elongation, and is involved in regulating angiogenesis and preserving endothelial homeostasis [1,2]. Notch1 signalling can transcriptionally regulate endothelial Ntn4 [5].

In breast cancer, Ntn4 expression is lower in invasive carcinoma compared to adjacent non-malignant tissues. Low Ntn4 expression is associated with poorer survival, and it is related to immune cell infiltration, such as positive correlation with CD8+ T cells, macrophages and neutrophils, and negative correlation with B cells and tumor purity [1]. In addition, Ntn4 may act as a tumor suppressor, as its loss in mice leads to earlier tumor onset, progression, and metastasis, and it can attenuate the Wnt signalling pathway by binding to Wnt ligands [3].

In hepatocellular carcinoma, systemic and hepatic Ntn4 levels are reduced, and hepatic expression of its receptors Neogenin and UNC5B are elevated in patients with portal vein invasion [2].

In endometrial cancer, EXOSC5 can up-regulate Ntn4 expression, which in turn activates c-MYC via the integrin β1/FAK/SRC pathway [4].

In conclusion, Ntn4 plays important roles in multiple biological processes and disease conditions. Its functions in promoting neurite growth, regulating angiogenesis, and its implications in cancers such as breast, liver, and endometrial cancers are significant. The use of mouse models, like the Ntn4 knockout in mice, has provided insights into its role in tumorigenesis, highlighting its potential as a target for cancer treatment and prognosis prediction.