Modulation of Notch signaling as a therapeutic approach for liver cancer

Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Aberrant Notch signaling has been mechanistically linked to cancer development including liver cancer. The two principal types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC). HCCs comprise over 80% of all liver cancers and are the 6(th) most common malignancy worldwide. Hepatocellular carcinoma is also a cancer with an extremely poor prognosis, being the 3(rd) commonest cause of cancer-related mortality. Accumulating evidence indicates that the role of Notch signaling in liver cancer is more complex than once thought and is dependent on the expression of specific Notch signaling components and the complex crosstalk with other signaling pathways. Currently there are a variety of gene therapy based approaches used to target Notch signaling in preclinical studies to successfully treat liver cancer including neutralizing antibodies, siRNA, shRNA and miRNA. The use of targeted anti-Notch therapy in the clinic to treat liver cancer will require considerable refinement of our current knowledge on the regulation of Notch signaling components and their effects in both normal and malignant liver cells in order to target specific Notch subunits which are critical to liver cancer tumorigenesis but not to the homeostasis of normal cells. Using this approach will reduce the major side effects, which are frequently seen in patients treated with GSIs to inhibit the entire Notch signaling pathway. Here our understanding of Notch signaling is reviewed, highlighting its function in liver cancer initiation, progress and opportunities for liver cancer therapies.