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Published on: October 30, 2013
Loss of Fibroblast Growth Factor Receptor 2 (FGFR2) Leads to Defective Bladder Urothelial Regeneration after
Sridhar T Narla1, Daniel S Bushnell1, Caitlin M Schaefer1
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Abstract:
Cyclophosphamide may cause hemorrhagic cystitis and eventually bladder urothelial cancer. Genetic determinants for poor outcomes are unknown. We assessed actions of fibroblast growth factor receptor (FGFR) 2 in urothelium after cyclophosphamide exposure. Conditional urothelial deletion of Fgfr2 (Fgfr2KO) did not affect injury severity or proliferation of keratin 14+ (KRT14+) basal progenitors or other urothelial cells 1 day after cyclophosphamide exposure. Three days after cyclophosphamide exposure, Fgfr2KO urothelium had defective regeneration, fewer cells, larger basal cell bodies and nuclei, paradoxical increases in proliferation markers, and excessive replication stress versus controls. Fgfr2KO mice had evidence of pathologic basal cell endoreplication associated with absent phosphorylated ERK staining and decreased p53 expression versus controls. Mice with conditional deletion of Fgfr2 in urothelium enriched for KRT14+ cells reproduced Fgfr2KO abnormalities after cyclophosphamide exposure. Fgfr2KO urothelium had defects up to 6 months after injury versus controls, including larger basal cells and nuclei, more persistent basal and ectopic lumenal KRT14+ cells, and signs of metaplasia (attenuated E-cadherin staining). Mice missing one allele of Fgfr2 also had (less severe) regeneration defects and basal cell endoreplication 3 days after cyclophosphamide exposure versus controls. Thus, reduced FGFR2/ERK signaling apparently leads to abnormal urothelial repair after cyclophosphamide exposure from pathologic basal cell endoreplication. Patients with genetic variants in FGFR2 or its ligands may have increased risks of hemorrhagic cystitis or urothelial cancer from persistent and ectopic KRT14+ cells.
Insights
Fibroblast growth factor receptor 2 (FGFR2) signaling is crucial for bladder urothelial repair after cyclophosphamide exposure. Reduced FGFR2 signaling causes abnormal regeneration and pathologic cell growth, potentially increasing cancer risk.
Area of Science:
- Urology
- Oncology
- Cell Biology
Background:
- Cyclophosphamide (CP) chemotherapy can induce hemorrhagic cystitis and bladder cancer.
- The genetic factors influencing poor outcomes after CP exposure remain largely unknown.
- Fibroblast growth factor receptor (FGFR) signaling plays a role in tissue repair and development.
Purpose of the Study:
- To investigate the role of FGFR2 in urothelial regeneration following CP-induced injury.
- To determine if FGFR2 signaling impacts the development of CP-induced bladder pathologies.
Main Methods:
- Conditional deletion of Fgfr2 in mouse urothelium (Fgfr2KO) and KRT14+ cells.
- Assessment of urothelial injury, regeneration, proliferation, and cell morphology after CP exposure.
- Analysis of molecular markers including phosphorylated ERK and p53, and E-cadherin staining.
Main Results:
- Fgfr2KO mice exhibited defective urothelial regeneration, increased replication stress, and pathologic basal cell endoreplication post-CP.
- Reduced FGFR2 signaling led to persistent defects, including larger basal cells, ectopic KRT14+ cells, and metaplasia, up to 6 months.
- Partial Fgfr2 deletion also resulted in regeneration defects and endoreplication after CP exposure.
Conclusions:
- Reduced FGFR2/ERK signaling impairs urothelial repair after CP exposure, driven by basal cell endoreplication.
- Genetic variants in FGFR2 may increase patient susceptibility to CP-induced hemorrhagic cystitis and urothelial cancer.
