Prostate cancer is caused by changes in several tumor suppressor genes including PTEN and p53, with loss of PTEN apparently important in carcinogenesis and loss of p53 important in development of biologically aggressive behavior, according to an article in the August 4th issue of Nature.

Up to 70 percent of men with prostate cancer have lost one copy of the PTEN gene at the time of diagnosis, and p53 is absent in a high number of patients with advanced prostate cancer.

The current research provides some of the first evidence that the phenomenon of cellular senescence, normally associated with stress and/or aging, also occurs in cancer both in animal models and in humans. Researchers suggest that drugs that support p53 function could delay progression of prostate cancer in PTEN-deficient prostate cancer by triggering cellular senescence.

"In attempting to clarify the role of the PTEN and p53 tumor suppressor genes in advanced prostate cancer cells, we unexpectedly discovered that acute loss of PTEN results in increased, not decreased p53 function. This works to suppress the further development of cancer," said Pier Paolo Pandolfi, MD, PhD, Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "If we can maintain a higher level of p53 in prostate cancer and induce cellular senescence, the disease should remain stable. This provides new opportunities for therapeutic intervention."

In animal model research, three sets of transgenic mouse models were generated with either the PTEN gene, Trp53 gene, or both genes deleted from the prostate. These mice were compared with normal (wild-type) mice in the same breeding system. The mice without PTEN experienced tumor growth. Those without Trp53 did not. Those with both genes removed had accelerated tumor growth.

Researchers next followed a cohort of 128 mice that were either normal or had the same genetic alterations as described above. All mice had magnetic resonance imaging twice weekly for detection of prostate tumors. While the normal mice and the mice without Trp53 had no tumors at six months, the mice without PTEN had small prostate tumors confined to the prostate. The mice both genes absent developed large prostate tumors and died by seven months. This showed that inactivation of Trp53 led to massive tumor growth and lethal prostate cancer only when PTEN was depleted or inactivated.

"We realized that the senescence program is intrinsic to all cells, acting as an emergency defense system for prostate cells that are en route to becoming cancerous," explained Zhenbang Chen, PhD, the paper's first author. "As long as the cancer cells remain in the state of cellular senescence, the tipping point to cancer growth will be prevented."

To determine whether their findings were relevant to human prostate cancer, the researchers performed immunohistochemical analysis of prostate tissues. They detected a marker for activation of the senescence pathway when PTEN was inactivated. Next, they examined early stage human prostate cancer sections stained for the senescence marker under high magnification. The senescence marker was seen in areas of hyperplasia that may precede the development of carcinoma.