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Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients
Hiroshi Tsuruta1, Hiroyuki Kishimoto, Takehiko Sasaki
1Department of Urology, Akita University School of Medicine, Akita, Japan.
Abstract:
PTEN is a tumor suppressor gene mutated in many human cancers. We used the Cre-loxP system to generate an urothelium-specific null mutation of Pten in mice [FabpCrePten(flox/flox) (FPten(flox/flox)) mice]. Histologic examination revealed that all FPten(flox/flox) mice exhibited urothelial hyperplasia in which component cells showed enlarged nuclei and increased cell size. With time, 10% of FPten(flox/flox) mice spontaneously developed pedicellate papillary transitional cell carcinomas (TCC). This type of tumor also arose in FPten(flox/flox) mice treated with the chemical carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine. FPten(flox/flox) urothelial cells were hyperproliferative and showed increased activation of the survival signaling molecules Akt and extracellular signal-regulated kinase. In humans, 53% of primary bladder cancer patients exhibited decreased or absent expression of PTEN protein in either the cytoplasm or nucleus of tumor cells. In early bladder cancers, PTEN expression was repressed in 42% of superficial papillary TCC but in only 8% of cases of carcinoma in situ (CIS). In advanced bladder cancers, PTEN protein was significantly reduced (particularly in the nucleus) in 94% of cases, and this decrease in PTEN correlated with disease stage and grade. Thus, PTEN deficiency may contribute to bladder cancer both by initiating superficial papillary TCC and by promoting the progression of CIS to advanced invasive and metastatic forms.
Insights
Loss of the PTEN tumor suppressor gene in mice causes urothelial hyperplasia and bladder tumors. PTEN deficiency in human bladder cancers correlates with advanced disease, suggesting its role in tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN is a critical tumor suppressor gene frequently altered in human cancers.
- Loss-of-function mutations in PTEN are implicated in various malignancies, but its specific role in bladder cancer initiation and progression requires further elucidation.
Purpose of the Study:
- To investigate the role of PTEN in urothelial carcinogenesis using a genetically engineered mouse model.
- To correlate PTEN expression levels with different stages and grades of human bladder cancer.
Main Methods:
- Generation of urothelium-specific Pten null mutant mice (FabpCrePten(flox/flox)) using the Cre-loxP system.
- Histological and molecular analyses of mouse bladders, including assessment of proliferation and signaling pathways (Akt, ERK).
- Immunohistochemical analysis of PTEN protein expression in human bladder tumor samples across different stages (carcinoma in situ, superficial papillary TCC, advanced bladder cancer).
Main Results:
- FPten(flox/flox) mice developed urothelial hyperplasia with enlarged cells and increased proliferation.
- Spontaneous and carcinogen-induced transitional cell carcinomas (TCC) arose in FPten(flox/flox) mice.
- PTEN protein was decreased or absent in 53% of human primary bladder cancers, with reduced expression correlating with advanced stage and higher grade. PTEN loss was observed in 42% of superficial TCC and 94% of advanced bladder cancers.
Conclusions:
- Urothelium-specific Pten deficiency in mice recapitulates key features of bladder cancer development and progression.
- PTEN loss is a significant event in human bladder cancer, contributing to both tumor initiation and advancement.
- Targeting PTEN loss may offer therapeutic strategies for bladder cancer treatment.
