Mouse Bladder Cancer Model Lacks Tumor Suppressor Genes

Cancer researchers have genetically engineered a line of mice to serve as a model of human bladder cancer through the combined deletion of the p53 and PTEN tumor suppressor genes from the animals' bladder epithelial cells.

Bladder cancer is the fifth most common malignancy and a major cause of cancer morbidity and mortality worldwide. So far, there have been few mouse models that properly replicate the invasive capabilities of this disease. The current study, which was published in the March 15, 2009, issue of the journal Genes & Development, described the creation of a new mouse model for invasive bladder cancer through the deletion of two tumor suppressor genes, p53 and PTEN.

In normal cells p53 is inactivated by its negative regulator, mdm2. When DNA damage or some other forms of stress occur, various pathways lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will either induce a cell cycle arrest to facilitate repair and survival of the cell or apoptosis to allow the damaged cell to die. While p53 acts to suppress tumor formation, the failure of p53 gene to function correctly has been estimated to lead to more than 50% of cancerous tumors.

PTEN (phosphatase and tensin homolog) is the name of a phospholipid phosphatase protein, and gene that encodes it. The PTEN gene is a human gene that acts as a tumor suppressor gene thanks to the role of its protein product in regulation of the cycle of cell division, preventing cells from growing and dividing too rapidly.

Investigators at Columbia University (New York, NY, USA) found that the combined deletion of p53 and PTEN from the animals' bladder epithelium led to the formation of invasive tumors. These findings supported earlier results that showed that inactivation of p53 and PTEN promoted tumorigenesis in human bladder cells and was correlated with poor survival in human tumors. The synergistic effects of p53 and PTEN deletion were mediated by deregulation of mammalian target of rapamycin (mTOR) signaling. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. The dysregulation of the mTOR pathway has been implicated as a contributing factor to various human disease processes, especially various types of cancer.

"We believe that this new mouse model of human bladder cancer will be invaluable to the field of bladder cancer research. Already it has provided a relevant preclinical model for therapeutic investigations and a strong rationale for targeting the mTOR signaling pathway in patients with invasive bladder cancer," said senior author Dr.Cory Abate-Shen, professor of urology, pathology, and cell biology at Columbia University.

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