Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes
Sayaka Sekiya, Atsushi Suzuki
Sayaka Sekiya, Atsushi Suzuki
Published November 1, 2012; First published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3914-3918. https://doi.org/10.1172/JCI63065.
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Category: Brief Report

Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes

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.

Authors

Sayaka Sekiya, Atsushi Suzuki

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Figure 1

Primitive ductules formed in ICC are derived from hepatocytes, rather than cholangiocytes.

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Primitive ductules formed in ICC are derived from hepatocytes, rather th...
(A) Experimental procedure to follow the lineage of hepatocytes and cholangiocytes in mouse liver. In the presence of TM, CreERT2 expressed from the Alb or CK19 genomic locus translocates into the nucleus and removes the loxP-flanked stop cassette from the R26R allele, leading to permanent heritable expression of the β-gal or YFP gene. (B) Representative images of liver from mice that drank normal water (left) or TAA-containing water (right) for 30 weeks. Tumoral macronodules only formed after TAA administration. (C and D) Immunohistochemical staining of CK19 (C, top row), X-gal staining (C, bottom row), and co-immunofluorescence staining of β-gal and EpCAM (D) were conducted for neoplastic nodules formed in the liver of Alb-CreERT2;R26RlacZ/+ mice and CK19-CreERT2;R26RlacZ/+ mice after 30 weeks’ TAA administration. DNA was stained with DAPI. Scale bars: 10 mm (B), 100 μm (C), and 50 μm (D).