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Fibroblast growth factor receptor 4, implicated in progression of islet cell carcinogenesis by its expression
1Hormone Research Institute, University of California, San Francisco, 94143-0534, USA.
Abstract:
Fibroblast growth factor receptor 4 (FGFR4) gene expression is activated in late-stage beta-cell tumors that develop in transgenic mice harboring SV40 large T antigen (Tag) gene that is under the transcriptional control of the insulin promoter (RIP-Tag). The FGFR4 gene was active in cell lines derived from tumors but not in cells derived from hyperplastic islets. We used both gain-of-function and loss-of-function FGFR4 transgenic mice to determine whether FGFR4 modulates islet cell tumorigenesis and, if so, to identify the nature of the effect. Both types of FGFR4 transgenic mice were viable and fertile and developed islet tumors when crossed with RIP-Tag mice. Remarkably, there was no significant perturbation in the tumorigenesis pathway resulting from either chronic up-regulation or absence of FGFR4 gene expression. Analyses included the incidence and size of tumors, rate of cell proliferation, cell density, and life span. We conclude that FGFR4 gene activation is a marker of but is not causal for beta-cell transformation.
Insights
Fibroblast growth factor receptor 4 (FGFR4) gene activation marks, but does not cause, beta-cell tumors in a mouse model. Studies in transgenic mice show FGFR4 does not significantly alter islet cell tumorigenesis.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Fibroblast growth factor receptor 4 (FGFR4) gene expression is upregulated in late-stage beta-cell tumors in RIP-Tag transgenic mice.
- FGFR4 gene activity is detected in tumor-derived cell lines but absent in hyperplastic islet cells.
Purpose of the Study:
- To investigate the role of FGFR4 in islet cell tumorigenesis using gain-of-function and loss-of-function models.
- To determine if FGFR4 modulates the development and progression of beta-cell tumors.
Main Methods:
- Generation of FGFR4 gain-of-function and loss-of-function transgenic mice.
- Crossing these mice with RIP-Tag transgenic mice to induce islet tumors.
- Analysis of tumor incidence, size, cell proliferation rates, cell density, and lifespan.
Main Results:
- Both FGFR4-overexpressing and FGFR4-deficient mice developed islet tumors when crossed with RIP-Tag mice.
- No significant alterations in tumorigenesis pathways were observed due to FGFR4 up-regulation or absence.
- Tumor incidence, size, proliferation, cell density, and lifespan remained largely unaffected.
Conclusions:
- FGFR4 gene activation is a consequence, not a cause, of beta-cell transformation.
- FGFR4 is a marker of, but not a driver for, beta-cell tumorigenesis in this model.