Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes
Sayaka Sekiya, Atsushi Suzuki
Sayaka Sekiya, Atsushi Suzuki
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3914-3918. https://doi.org/10.1172/JCI63065.
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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 3

Notch signal activation is significant not only for conversion of hepatocytes into biliary lineage cells at the onset of ICC, but also the malignancy and progression of ICC.

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Notch signal activation is significant not only for conversion of hepato...
(A–C) Immunofluorescence staining of CK19 was conducted in the liver of R26RNotch/+ mice (A), Alb-CreERT2;R26RNotch/+ mice (B), and Alb-CreERT2;Hes1fl/fl mice (C) after 14 weeks of TAA administration. (D) The percentages of cells immunoreactive for CK19 in the liver of R26RNotch/+, Alb-CreERT2;R26RNotch/+, and Alb-CreERT2;Hes1fl/fl mice were calculated after counting approximately 3,000 cells per field of vision in 3 discontinuous liver tissue slides for 3 individual mice after 14 weeks of TAA administration. The data represent mean ± SD. (E) Immunofluorescence staining of CK19 was conducted in the liver of Alb-CreERT2;R26RYFP/Notch mice after 8 weeks of TAA administration. (F and G) Representative images of the liver from R26RNotch/+ mice (F) and Alb-CreERT2;R26RNotch/+ mice (G) after 14 weeks of TAA administration. Developing neoplastic nodules are only found in the liver of Alb-CreERT2;R26RNotch/+ mice. CV, central vein; PV, portal vein. DNA was stained with DAPI. Scale bars: 500 μm (A–C), 100 μm (E), and 5 mm (F and G).