Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

PTEN and prostate cancer--the devil is in the doses

27.10.2003


Cancer is a complex disease where multiple genetic and environmental factors contribute to risk. Its onset and progression depends on the combination of a series of genetic disruptions rather than on a single event. At a genetic level, it is not just presence or absence of a gene (or a mutated version of the gene) that causes disease, but as Pier Paolo Pandolfi and colleagues report, protein "dose"--that is, the level of remaining activity--also influences cancer progression.



Focusing on the tumor suppressor gene PTEN, the researchers created a mouse model system to study tumor progression in prostate cancer. PTEN is among the most commonly mutated tumor suppressor genes in human cancer. And like many other tumor suppressors, PTEN targets proteins in signaling pathways that regulate cell growth and apoptosis in healthy tissue and contributes to cancer when dysfunctional. Humans, as diploid organisms, generally have two versions of most genes, including PTEN. In the event that one copy is damaged or lost, gene function is usually maintained by the other copy. In the classic definition of a tumor suppressor, both copies must be lost for a tumor to occur. Yet in many cases of advanced cancer, including prostate cancer, only one copy is lost at the time a patient shows symptoms. It is then not unreasonable to hypothesize that the degree of remaining PTEN activity controls the course of the disease: loss of one copy could influence tumor initiation, while further slight reductions might be sufficient to facilitate the invasion and metastatic behavior of late-stage cancers.

Pandolfi and colleagues chose two strategies to investigate this hypothesis. In the first approach, they genetically engineered one series of mice with minimal levels of murine PTEN protein (complete loss results in embryo death). This novel 25%–35% active PTEN "hypomorphic" strain of mice, which appears to retain the minimum level of PTEN needed to survive embryonic development, adds to existing strains of fully normal and 50% active PTEN mice. In order to model the full loss of PTEN protein, the researchers generated another series of mice in which PTEN genes were selectively disabled in the prostate only. The researchers found that subtle reductions in PTEN dose did indeed produce progressive changes in the biology of the tumor, while mice having no functional PTEN genes showed the most invasive and aggressive cancers. These results, the researchers say, show that PTEN plays a "crucial dose-dependent role in prostate cancer tumor suppression" and that progressive reduction of gene function induces progressive changes in the quantity and quality of molecular and pathological effects on the pathway to full-blown cancer.


By coupling the molecular genetics and dose of PTEN protein with the physiological progression of cancer in the prostate, these new mouse models may not only shed light on cancer progression in humans, but also help bolster diagnostic, prognostic, and therapeutic techniques. While evaluation of tumor status has traditionally been determined by pathological analysis of tissue samples, these new models allow scientists to pair anatomical stages with underlying molecular events--such as the expression level of a single gene or protein--to allow more accurate assessments. These molecular profiles can also help researchers design targeted, more efficient prostate cancer treatments. For example, if prostate tissue is hypersensitive to PTEN in humans--which the results suggest may be the case, since male mice with only 30% of normal PTEN levels show massive and selective enlargement of the prostate, and even invasive tumors--then ongoing monitoring of PTEN levels could help tailor therapies based on promoting PTEN expression. For patients with complete loss of PTEN function, where this would not be an option, inhibiting the proteins made overactive through PTEN loss could prove effective. And these approaches could well hold true for other cancers involving PTEN, including endometrial, brain, and breast cancer.


###
Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, et al. (2003) PTEN dose dictates cancer progression in the prostate. DOI: 10.1371/journal.pbio.0000059

All works published in PLoS Biology are open access. Everything is immediately available without cost to anyone, anywhere -- to read, download, redistribute, include in databases, and otherwise use -- subject only to the condition that the original authorship is properly attributed. Copyright is retained by the author. The Public Library of Science uses the Creative Commons Attribution License.

This article, which appears in PDF form online on October 27, 2003, is presented as a pre-issue publication. The article will appear both as HTML (along with the PDF) and in print in our December 22, 2003 issue.

CONTACT:
Dr. Pier Paolo Pandolfi
Molecular Biology Program and Department of Pathology
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, Box 110
New York, NY 10021
United States of America
212-639-6168
212-717-3102 (fax)
p-pandolfi@ski.mskcc.org

Barbara Cohen | PLoS
Further information:
http://www.plos.org/downloads/plbi-01-03-pandolfi.pdf

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>