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 New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology

nachricht Alzheimer’s: Cellular Mechanism Provides Explanation Model for Declining Memory Performance
21.09.2016 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

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: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

Im Focus: New laser joining technologies at ‘K 2016’ trade fair

Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.

K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

Using mathematical models to understand our brain

16.09.2016 | Event News

 
Latest News

Chains of nanogold – forged with atomic precision

23.09.2016 | Life Sciences

New leukemia treatment offers hope

23.09.2016 | Health and Medicine

Self-assembled nanostructures hit their target

23.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>