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Updated: Aug 4, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Different combinations of genetic/epigenetic alterations inactivate the p53 and pRb pathways in invasive human
S Sarkar1, K P Jülicher, M S Burger
1Department of Human Oncology, University of Wisconsin Medical School and Comprehensive Cancer Center, Madison 53792, USA.
Abstract:
Inactivation of both the pRb (pRb-cyclin D1/cyclin-dependent kinase 4/6-p16) and p53 (p53-p21(WAF1)-p14(ARF)) pathways is thought to be essential for immortalization in vitro and malignant transformation in vivo. We identified different combinations of pRb and p53 pathway alterations in 12 invasive transitional cell carcinomas (TCCs) and addressed the functional significance of the different combinations observed. Results showed four combinations of alterations including -pRb/-p53 (ie., pRb inactivated in the pRb pathway and p53 inactivated in the p53 pathway; four TCCs), -p16/-p53 (four TCCs), -p16/-p21(WAF1) (one TCC), and -p16/ -p14(ARF) (two TCCs). These groups include two new combinations (ie., -p16/-p53 and -p16/-p21(WAF1)) not reported previously for TCCs. An alteration in the key components of the p53 pathway was not detected in one invasive TCC that had inactivated p16. Note that all four TCCs with inactivated pRb had mutant p53; thus, the combinations of -pRb/ -p21(WAF1) and -pRb/-p14(ARF) were not observed. Only two of eight TCCs with altered p16 had concomitant p14(ARF) loss, demonstrating that simultaneous inactivation of these two 9p21INK4a tumor suppressor genes is not obligatory. To determine the biological phenotypes of TCCs with different combinations of pRb and p53 pathway alterations, their downstream responses to gamma radiation were studied in vitro. As expected, none of eight TCCs with mutant p53 responded to gamma radiation by elevation of p53, p21(WAF1), or mdm2 or by cell cycle arrest. Only two of four TCCs with wild-type p53 and wild-type pRb (the combination of -p16/-p14(ARF)) showed normal downstream responses to gamma radiation and underwent cell cycle arrest. Two TCCs with wild-type pRb and wild-type p53 (the combination of -pl6/-p21(WAF1) and one TCC with -p16) failed to show cell cycle arrest in response to radiation. This was attributed to the absence of p21(WAF1) in one TCC. In summary, these data support a model of invasive bladder cancer pathogenesis in which both the pRb and p53 pathways are usually inactivated and the biology of the tumor is impacted by the mechanism of their inactivations.
Insights
Alterations in the retinoblastoma (pRb) and p53 pathways are crucial for bladder cancer development. This study identified novel combinations of these pathway alterations and their impact on tumor response to radiation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Inactivation of the pRb and p53 pathways is critical for cell immortalization and malignant transformation.
- Understanding the specific combinations of these pathway alterations in transitional cell carcinoma (TCC) is essential for elucidating bladder cancer pathogenesis.
Purpose of the Study:
- To identify and characterize distinct combinations of pRb and p53 pathway alterations in invasive TCCs.
- To investigate the functional significance of these combinations on tumor biology, specifically in response to gamma radiation.
Main Methods:
- Analysis of pRb and p53 pathway component alterations in 12 invasive TCC samples.
- In vitro studies assessing downstream responses to gamma radiation, including p53, p21(WAF1), mdm2 elevation, and cell cycle arrest.
Main Results:
- Four combinations of pRb/p53 pathway alterations were identified, including two previously unreported for TCC: -p16/-p53 and -p16/-p21(WAF1).
- Tumors with mutant p53 did not respond to gamma radiation. Only a subset of tumors with wild-type pRb and wild-type p53 exhibited normal radiation response and cell cycle arrest.
- Simultaneous inactivation of the 9p21INK4a tumor suppressor genes (p16 and p14(ARF)) was not obligatory.
Conclusions:
- Both pRb and p53 pathways are typically inactivated in invasive bladder cancer.
- The specific mechanisms of pRb and p53 pathway inactivation influence the tumor's biological phenotype and response to genotoxic stress.
- These findings support a model where combined pathway inactivation drives bladder cancer progression.
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