Prostate cancer, the second leading cause of cancer death for men in the United States, is caused by changes in several tummor suppressor genes including PTEN and p53. 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.
Scientists at Memorial Sloan-Kettering Cancer Center have found an unexpected effect of the interaction of these two genes in early stage prostate cancer. In a study published in the August 4 issue of Nature, researchers found that prostate tumor growth is arrested through a biological process called cellular senescence, in which cells stop proliferating and remain alive but fail to respond to normal growth signals.
This research provides some of the first evidence that this phenomenon, 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 this experiment, three sets of transgenic mouse models were generated with either the Pten gene, Trp53 gene, or both Pten and Trp53 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 without both Pten and Trp53 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.