Discovery may aid in diagnosis, prognosis, and possibly prevention
NEW YORK, NY – October 27 – In patients with prostate cancer, one change that can be seen at the molecular level is the loss of the PTEN tumor suppressor gene, a gene responsible for restricting cell proliferation. One or both copies of the PTEN gene are found to have been lost in 70 percent of prostate cancer patients at the time of diagnosis. It has generally been believed that one remaining copy would still protect against tumor progression to advanced metastatic cancer.
But now, for the first time, scientists at Memorial Sloan-Kettering Cancer Center have established mouse models for prostate cancer that have varying "doses" or amounts of Pten protein produced from the remaining gene. Their results show that the activity of the single Pten gene does not necessarily protect against prostate cancer. Instead, the dose determines whether the tumor will become either an aggressive cancer or take a slow path towards microscopic features of growth, but remain benign. This new understanding of the natural history of the disease could allow researchers to develop novel clinical strategies to diagnose, treat, and possibly prevent prostate cancer. This article will appear both as HTML and in print in the December 23, 2003 issue of the new, open access journal published by the Public Library of Science. It appears in PDF form online as a pre-issue publication on October 27, 2003 at www.plosbiology.org.
"We have shown that prostate cancer development is not just affected by mutation and loss of the PTEN gene but that its progression is dose-dependent on the PTEN protein, which we have measured for the first time," said Pier Paolo Pandolfi, M.D., Ph.D., Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "Two men, each with one PTEN gene left, could have totally different disease outcomes depending on the actual dose of PTEN protein coming from that gene."
Earlier studies by Drs. Pier Paolo Pandolfi and Antonio Di Cristofano had demonstrated that loss of the Pten tumor suppressor gene in mice is responsible for a variety of malignant tumors. In humans, these were shown to include melanoma and cancers of the breast, prostate, and brain. Although the loss of just one Pten gene is enough to affect cell signaling, the loss has only been associated with slow-growing, mild lesions in the mouse prostate, comparable to early stages of the human disease. Therefore, many scientists in the field assumed that one copy of the Pten gene was still sufficient to prevent the progression to malignant cancer, in agreement with the classic definition of tumor suppressor genes.
To test this assumption, two sets of mouse models were generated. In one, the Pten gene was engineered to be removed completely from the prostate only (whole body deletion cannot be studied since it causes a lethal defect in the embryo). In the second model, mice were engineered to have only one half-active copy of the Pten gene left (roughly 30 percent protein level). In stark contrast to mice with one gene copy, the mice with no Pten gene showed aggressive, invasive prostate cancer that developed in just a short period, perhaps suggesting that the major danger in having only one copy of the Pten gene (50 percent of the normal protein level) would be to lose it (and go to zero percent). However, the mice with one half-active gene also developed prostate tumors while those with the fully active copy did not. This refuted the notion that only complete loss of the Pten gene can cause prostate cancer and instead suggests that prostate tumor development correlates closely with the actual Pten protein level.
"We analyzed the mice at a time when they should have been healthy but instead found massive prostate enlargement and cancer," explained Lloyd Trotman, Ph.D., a member of Dr. Pandolfi's Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and a first author of the study along with Masaru Niki M.D., Ph.D. "Most importantly, this showed that dropping the Pten protein dose slightly below the 50 percent level has dramatic consequences for disease progression in just a short period."
"This study shows the consequences of serial reductions in a critical gene on prostate cancer development and progression," said Dr. Howard Scher, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering. "It shifts the focus from targets of the PTEN gene to the PTEN protein itself. Restoring the function of the gene to stabilize the PTEN level may be clinically beneficial. These findings also show that to understand an individual's prognosis and to optimize the therapeutic approach to an individual patient's tumor, it will be necessary to determine the absolute level of key signaling proteins, and not simply whether the protein is present or absent. Developing these methods is an area of active investigation."
The study's co-authors include Zohar A. Dotan, Jason A. Koutcher, Antonio Di Cristofano, Alan S. Khoo, and Carlos Cordon-Cardo of Memorial Sloan-Kettering; Andrew Xiao and Terry Van Dyke of University of North Carolina at Chapel Hill; Pradip Roy-Burman of Keck School of Medicine, UCLA; and Norman Greenberg of Baylor College of Medicine. The study was supported, in part, by grants from the National Cancer Institute, Memorial Sloan- Kettering, and by I.T. Hirschl/M. Weill Caulier Foundation.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.