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Updated: Apr 22, 2026
The Influence of Liver Resection on Intrahepatic Tumor Growth
Published on: April 9, 2016
Differential effects of targeting Notch receptors in a mouse model of liver cancer
Erik G Huntzicker1, Kathy Hötzel, Lisa Choy
1Pathology Department Biomarker Group, Gilead Sciences, Foster City, CA.
Unlabelled:
Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question, we utilized antibodies to specifically target Notch1, Notch2, Notch3, or jagged1 (Jag1) in a mouse model of primary liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas). We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant HCC- and CCA-like tumors. Inhibition of the Notch ligand, Jag1, had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, because Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples.
Conclusions:
These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer.
Insights
Targeting Notch2 signaling in liver cancer shows promise. Inhibiting Notch2 or its ligand Jag1 reduced tumor burden in mice, suggesting a new therapeutic strategy for primary liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA).
- The Notch signaling pathway is crucial for liver development and implicated in liver cancer.
- The specific roles of individual Notch pathway components in liver cancer remain unclear.
Purpose of the Study:
- To investigate the predominant roles of Notch receptors (Notch1, Notch2, Notch3) and the Notch ligand Jagged1 (Jag1) in primary liver cancer.
- To evaluate the therapeutic potential of targeting specific Notch pathway members in a mouse model of liver cancer.
Main Methods:
- Utilized specific antibodies to inhibit Notch1, Notch2, Notch3, and Jag1 in a mouse model of liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas).
- Assessed the impact of inhibition on tumor burden and tumor type proportions.
- Examined Notch2 and Jag1 expression and Notch2 signaling activation in human HCC samples.
Main Results:
- Inhibition of Notch2 significantly reduced tumor burden by eliminating HCC- and CCA-like tumors.
- Jag1 inhibition yielded similar results, suggesting cooperation with Notch2.
- Notch1 inhibition altered tumor composition, decreasing HCC-like tumors while increasing CCA-like tumors.
- Notch2 and Jag1 were found to be expressed in, and Notch2 signaling activated in, a subset of human HCC samples.
Conclusions:
- Notch2 and Jag1 play critical roles in driving primary liver cancer.
- Notch1 has distinct effects on different liver cancer types.
- Inhibition of Notch2 signaling presents a potential novel therapeutic strategy for liver cancer treatment.
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