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Updated: May 22, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models
Dorothy M French1, Benjamin C Lin, Manping Wang
1Department of Pathology, Genentech, Inc, South San Francisco, California, United States of America.
Abstract:
The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.
Insights
Fibroblast growth factor receptor 4 (FGFR4) is essential for liver tumor development. Blocking FGFR4 with an antibody inhibited hepatocellular carcinoma growth, suggesting it as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling is crucial for development and physiology.
- Dysregulated FGF-FGFR signaling is implicated in tumor development and progression.
- The FGFR4-FGF19 axis is linked to hepatocellular carcinoma (HCC) development.
Purpose of the Study:
- To investigate the role of FGFR4 in hepatocarcinogenesis.
- To evaluate the therapeutic potential of targeting FGFR4 in liver cancer.
Main Methods:
- Generated FGFR4 knockout mice crossed with FGF19 transgenic mice to assess tumor development.
- Developed and utilized a blocking anti-FGFR4 monoclonal antibody (LD1).
- Assessed antibody effects on FGF binding, FGFR4 signaling, cell proliferation, and tumor growth in preclinical models.
Main Results:
- FGFR4 knockout mice failed to develop liver tumors, indicating FGFR4's requirement for hepatocarcinogenesis.
- The anti-FGFR4 antibody (LD1) inhibited FGF binding, FGFR4 signaling, and cancer cell proliferation in vitro.
- LD1 treatment suppressed tumor growth in a preclinical liver cancer model.
- FGFR4 expression was elevated in liver cancer and other cancers compared to normal tissues.
Conclusions:
- FGFR4 plays a critical role in the development and progression of hepatocellular carcinoma.
- Targeting FGFR4 represents a potential novel therapeutic strategy for liver cancer and possibly other malignancies.
