Presented October 25th - 28th, 2007 at the 2007 Urological Research Society (URS) Meeting - Napa, California

Introduction: Phosphatase and tensin homolog (PTEN) is a multifunctional phosphatase whose substrate is phosphatidylinositol-3,4,5-triphosphate (PIP3), and it is also a ubiquitously expressed tumor suppressor gene that down-regulates phosphatidylinositol-3-kinases (PI3Ks). Recent studies have found a higher frequency of the PTEN tumor-suppressor gene alterations in invasive bladder cancer compared with superficial disease, suggesting that PTEN inactivation is important in the progression. A role of PTEN in bladder cancer progression, however, remains unclear. The aim of this study is to clarify the role of PTEN in urothelial carcinogenesis.

Methods: In order to generate PTEN-deficient mice using the Cre-loxP system, we selectively inactivated PTEN in murine tissues in which the Fabp-Cre promoter is active. We analyzed the modifying effects on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced urinary bladder carcinogenesis during the initiation and post-initiation phases in wild type and PTEN-deficient mice. To determine PTEN protein expression in the cytoplasm and nucleus of tumor cells only, we performed immunostaining on samples from 68 patients with primary bladder cancers.

Results: Histological examination revealed that all Pten-deficient mice exhibited urothelial hyperplasia in which component cells showed enlarged nuclei and increased cell size. With time, 10% of Pten-deficient mice spontaneously developed pedicellate papillary transitional cell carcinomas (TCCs). This type of tumor also arose in Pten-deficient mice treated with the chemical carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Pten-deficient urothelial cells were hyperproliferative and showed increased activation of the survival signaling molecules Akt and extracellular signal-regulated kinases (Erks). 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 and this decrease in PTEN correlated with disease stage and grade.

Conclusions: The present results indicate that PTEN plays an important role in regulating normal growth of urothelium and one of the important key regulators in urothelial carcinogenesis. Furthermore, PTEN may be important for the prevention of urothelium carcinogenic transformation by carcinogens, and the PTEN-deficient mouse is a novel model for bladder cancer.

Authors: Tsuruta H, Kishimoto H, Sasaki T, Horie Y, Natsui M, Shibata Y, Hamada K, Yajima N, Kawahara K, Sasaki M, Tsuchiya N, Enomoto K, Mak TW, Nakano T, Habuchi T, and Suzuki A

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