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.
"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, a researcher in Dr. Pier Paolo Pandolfi's laboratory and 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 area of hyperplasia that may precede the development of carcinoma.
"This study helps us to understand the molecular alterations and mechanisms that can lead to the development of prostate cancer and identifies targets for therapeutic attack," said Dr. Howard Scher, Chief of the Genitourinary Service at Memorial Sloan-Kettering and a co-author of the study. "We are also working to use these models to design more effective clinical tests by determining which combination of agents is most likely to be effective. We are already testing specific drugs to restore PTEN function, based on its role in prostate cancer development and progression."
The study's co-authors are Lloyd C. Trotman, David Shaffer, Hui-Kuan Lin, Zohar A. Dotan, Masaru Niki, Jason A. Koutcher, Thomas Ludwig, William Gerald, and Carlos Cordon-Cardo of Memorial Sloan-Kettering. The study was supported, in part, by grants from the National Institutes of Health.
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