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Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes

Journal of Clinical Investigation · 2012 · 362 citations · 17 references

TL;DR

Intrahepatic cholangiocarcinoma is the second most common primary liver cancer, traditionally thought to arise from cholangiocytes but evidence of viral hepatitis co‑occurrence suggests a hepatocyte origin. The study aimed to determine whether ICC originates from hepatocytes or cholangiocytes. Using a mouse model with heritable, cell‑type specific reporters for hepatocytes and cholangiocytes, the authors traced lineage to assess tumor origin. The lineage tracing revealed that ICC arises from hepatocytes converting into biliary lineage cells via Notch activation, which is essential for tumor initiation and progression, highlighting a new pathogenic mechanism and therapeutic target.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy in the liver. ICC has been classified as a malignant tumor arising from cholangiocytes; however, the co-occurrence of ICC and viral hepatitis suggests that ICC originates in hepatocytes. In order to determine the cellular origin of ICC, we used a mouse model of ICC in which hepatocytes and cholangiocytes were labeled with heritable, cell type–specific reporters. Our studies reveal that ICC is generated by biliary lineage cells derived from hepatocytes, rather than cholangiocytes. Additionally, we found that Notch activation is critical for hepatocyte conversion into biliary lineage cells during the onset of ICC and its subsequent malignancy and progression. These findings will help to elucidate the pathogenic mechanism of ICC and to develop therapeutic strategies for this refractory disease.