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Updated: Apr 23, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer
Mirentxu Santos1,2, Mónica Martínez-Fernández1,2, Marta Dueñas1,2
1Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.
Abstract:
Bladder cancer is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here, we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate bladder cancer development. The characterization of the mouse tumors revealed multiple molecular features of human bladder cancer, including the activation of E2F transcription factor and subsequent Ezh2 expression and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial bladder cancer. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirmed the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human patients with superficial bladder cancer is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial bladder cancer and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.
Insights
Inactivating retinoblastoma (Rb) genes in mice initiates bladder cancer. This study reveals an Rb-E2F-Ezh2 pathway crucial for bladder tumor development and recurrence in humans.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Bladder cancer frequently involves retinoblastoma (Rb) pathway inactivation and epigenetic changes.
- The interplay between Rb pathway inactivation and epigenetic alterations in bladder cancer remains unclear.
Purpose of the Study:
- To investigate the role of Rb family genes in bladder cancer initiation.
- To establish a genetically defined mouse model for high-grade superficial bladder cancer.
- To elucidate the molecular mechanisms linking Rb inactivation to bladder tumorigenesis.
Main Methods:
- In vivo inactivation of Rb family genes in mouse urothelium.
- Molecular characterization of resultant mouse tumors.
- Whole transcriptional profiling of mouse and human bladder tumors.
- Analysis of E2F and Ezh2 expression in human bladder cancer patients.
Main Results:
- Rb family gene inactivation in mouse urothelium induced bladder cancer.
- Mouse tumors exhibited molecular features similar to human bladder cancer, including E2F activation and Ezh2 expression.
- Transcriptional analysis revealed a conserved role for Ezh2 in gene downregulation across species.
- Elevated E2F and Ezh2 expression correlated with increased tumor recurrence and progression in human patients.
Conclusions:
- Rb-E2F-Ezh2 axis disruption promotes bladder tumor development.
- This study provides a valuable genetically defined model for high-grade superficial bladder cancer.
- Understanding the Rb-E2F-Ezh2 axis offers potential therapeutic targets for bladder cancer.
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