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An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary
G A Niehans1, R A Kratzke, M K Froberg
1Department of Pathology, Minneapolis Department of Veterans Affairs Medical Center, University of Minnesota Medical School, 55417, USA.
Abstract:
The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.
Insights
Most bladder cancers (70%) disrupt the G1 cell cycle checkpoint proteins, including retinoblastoma (Rb) and p16INK4a. Cyclin D1 overexpression correlates with better outcomes, while Rb loss completely abolishes the G1 checkpoint.
Area of Science:
- Oncology
- Cell Biology
- Molecular Pathology
Background:
- The G1 cell cycle checkpoint is crucial for regulating cell division and preventing uncontrolled proliferation.
- Alterations in G1 checkpoint proteins like retinoblastoma (Rb), cyclin D1, and p16INK4a are common in human cancers, leading to abrogated cell cycle control.
- Understanding these alterations in bladder cancer is vital for identifying potential therapeutic targets and prognostic markers.
Purpose of the Study:
- To investigate the frequency and significance of alterations in key G1 checkpoint proteins (Rb, p16INK4a, cyclin D1) and p53 in invasive transitional cell carcinomas of the urinary bladder.
- To determine the correlation between these protein alterations and clinicopathological features, including patient survival.
- To elucidate the role of these proteins in the dysregulation of the G1 cell cycle checkpoint in bladder cancer.
Main Methods:
- Immunohistochemistry was employed to assess the expression levels of Rb, p16INK4a, cyclin D1, and p53 in 79 invasive bladder carcinoma samples.
- Analysis included quantifying protein loss (Rb, p16INK4a) and overexpression (cyclin D1, p53 accumulation).
- Multivariate survival analysis was performed to correlate protein status with patient outcomes.
Main Results:
- Loss of Rb protein was observed in 29% of cases, inversely correlated with p16INK4a loss (19%).
- Cyclin D1 overexpression occurred in 27% of tumors, exclusively in those retaining Rb protein.
- Aberrant p53 accumulation was found in 63% of tumors, without correlation to other studied proteins. Overall, 70% of bladder carcinomas exhibited abnormalities in at least one G1 checkpoint protein (Rb, p16INK4a, cyclin D1).
- Cyclin D1 overexpression was associated with less aggressive disease and a favorable prognosis, while Rb, p16INK4a, and p53 status did not show statistical significance as prognostic factors.
Conclusions:
- The majority of bladder carcinomas display defects in G1 restriction point proteins, highlighting the critical role of cell cycle dysregulation in tumorigenesis.
- The findings support a model where cyclin D1 and p16INK4a cooperate in cell cycle dysregulation, but complete loss of Rb protein abrogates the G1 checkpoint.
- These alterations represent potential indicators of bladder cancer progression and patient outcome.
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