Scientists Discover Anti-cancer Mechanism That Arrests Early Prostate Cancer

Scientists at Memorial Sloan-Kettering Cancer Center have found anunexpected effect of the interaction of these two genes in early stageprostate cancer. In a study published in the August 4 issue of Nature,researchers found that prostate tumor growth is arrested through abiological process called cellular senescence, in which cells stopproliferating and remain alive but fail to respond to normal growthsignals.

This research provides some of the first evidence that thisphenomenon, normally associated with stress and/or aging, also occursin cancer both in animal models and in humans. Researchers suggest thatdrugs that support p53 function could delay progression of prostatecancer in Pten-deficient prostate cancer by triggering cellularsenescence.

"In attempting to clarify the role of the Pten and p53 tumorsuppressor genes in advanced prostate cancer cells, we unexpectedlydiscovered that acute loss of Pten results in increased, not decreasedp53 function. This works to suppress the further development ofcancer," said Pier Paolo Pandolfi, MD, PhD, Head of the Molecular andDevelopmental Biology Laboratory at Memorial Sloan-Kettering and thestudy's senior author. "If we can maintain a higher level of p53 inprostate cancer and induce cellular senescence, the disease shouldremain stable. This provides new opportunities for therapeuticintervention."

In this experiment, three sets of transgenic mouse models weregenerated with either the Pten gene, Trp53 gene, or both Pten and Trp53genes deleted from the prostate. These mice were compared with normal(wild type) mice in the same breeding system. The mice without Ptenexperienced tumor growth. Those without Trp53 did not. Those with bothgenes removed had accelerated tumor growth.

Researchers next followed a cohort of 128 mice that wereeither normal or had the same genetic alterations as described above.All mice had magnetic resonance imaging twice weekly for detection ofprostate tumors. While the normal mice and the mice without Trp53 hadno tumors at six months, the mice without Pten had small prostatetumors confined to the prostate. The mice without both Pten and Trp53developed large prostate tumors and died by seven months. This showedthat inactivation of Trp53 led to massive tumor growth and lethalprostate cancer only when Pten was depleted or inactivated.

"We realized that the senescence program is intrinsic to allcells, acting as an emergency defense system for prostate cells thatare en route to becoming cancerous," explained Zhenbang Chen, PhD, aresearcher in Dr. Pier Paolo Pandolfi's laboratory and the paper'sfirst author. "As long as the cancer cells remain in the state ofcellular senescence, the tipping point to cancer growth will beprevented."

To determine whether their findings were relevant to humanprostate cancer, the researchers performed immunohistochemical analysisof prostate tissues. They detected a marker for activation of thesenescence pathway when PTEN was inactivated. Next, they examined earlystage human prostate cancer sections stained for the senescence markerunder high magnification. The senescence marker was seen in area ofhyperplasia that may precede the development of carcinoma.

"This study helps us to understand the molecular alterationsand mechanisms that can lead to the development of prostate cancer andidentifies targets for therapeutic attack," said Dr. Howard Scher,Chief of the Genitourinary Service at Memorial Sloan-Kettering and aco-author of the study. "We are also working to use these models todesign more effective clinical tests by determining which combinationof agents is most likely to be effective. We are already testingspecific drugs to restore PTEN function, based on its role in prostatecancer development and progression."

The study's co-authors are Lloyd C. Trotman, David Shaffer, Hui-KuanLin, 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 NationalInstitutes of Health.

Memorial Sloan-Kettering Cancer Center is the world's oldestand largest institution devoted to prevention, patient care, research,and education in cancer. Our scientists and clinicians generateinnovative approaches to better understand, diagnose, and treat cancer.Our specialists are leaders in biomedical research and in translatingthe latest research to advance the standard of cancer care worldwide.