Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Master Molecular Switch May Prevent the Spread of Cancer Cells to Distant Sites in the Body

18.03.2009
Researchers at the University of Pennsylvania School of Medicine have identified a master switch that might prevent cancer cells from metastasizing from a primary tumor to other organs.

The switch is a protein that, when in the “on” position, maintains the normal character of cells that line the surface of organs and body cavities. These epithelial cells are the type of cell from which most solid tumors arise.

However, when the switch is turned “off” or absent, epithelial cells acquire characteristics of another cell type, called mesenchymal cells, and gain the ability to migrate and move away from the primary tumor. The researchers report their findings in this month’s issue of Molecular Cell.

Understanding how this switch works may one day lead to a drug that controls cancer cell metastasis and tissue fibrosis.

This change in cell motility is called the epithelial to mesenchymal transition, or EMT, and is an important process during the development of embryos. But when the transition is aberrantly reactivated in adults it can have dire physiological consequences, leading to cancer metastasis as well as other disease processes such as tissue fibrosis. Fibrotic tissue is a hallmark of organ failure, as in liver cirrhosis or kidney failure.

The master-switch is called the Epithelial Splicing Regulatory Protein, and comes in two closely related versions, ESRP1 and ESRP2. These proteins are able to change how RNAs that are produced from genes are spliced together. This is achieved by splicing different exons -- the sequence of DNA that codes information for protein synthesis -- together in different ways so that there can be more than one messenger RNA (mRNA) produced from the same gene. These mRNAs then go on to make different proteins.

The mRNA for Fibroblast Growth Factor Receptor 2 (FGFR2) is the focus of the Molecular Cell study. FGFR2 mRNA has two forms, one called IIIb, which is expressed in epithelial cells and IIIc, which is expressed in mesenchymal cells. The protein that is made from the IIIb form interacts with factors outside the cell that promote the epithelial cell behavior, that is to remain stationary. When the IIIc form is aberrantly produced in cancer cells derived from epithelial cells, the resulting FGFR2 protein type no longer promotes the epithelial cell identity, and switches to the mesenchymal cell type, which has the ability to detach from its primary site, invade local tissue and migrate, or metastasize to distant sites of the body.

“If we can find a way to maintain expression of ESRP1 and 2 in epithelial cells, then it might be possible to prevent metastasis or control fibrosis,” notes corresponding author Russ P. Carstens, MD, Assistant Professor of Medicine. “ESRP1 and ESRP2 are necessary for splicing FGFR2 mRNA in the epithelial cell manner. This is one of few known splicing factors that operate in a clear cut cell-type-specific manner. Epithelial cells, which make up the lining of organs, are the only cells that produce ESRP1 and ESRP2.”

To discover ESRP1 and ESRP2, the team used a high-throughput genetic screen for rare proteins developed by collaborator and co-author John B. Hogenesch, PhD, Associate Professor of Pharmacology, an innovator in the use of these types of screens. In addition, Claude Warzecha, a graduate student in the Carstens lab, played a key role in the completion of the screen.

The screen consists of about 15,000 different cDNAs (DNA that has been synthesized from messenger RNAs) that each express a different gene and are arrayed on plates so that each well of the plate expresses only one individual gene product. The Carstens lab developed a splicing “reporter” that makes cells express a firefly luciferase gene and “glow” when it is spliced in the epithelial cell pattern. Cells with this reporter were individually placed over wells containing each cDNA and cells that “glowed, indicated those cDNAs that produced proteins that promoted the epithelial splicing program. It was from this screen that ESRP1 and ESRP2 emerged.

In ongoing work, the team found that ESRP1 and ESRP2 are critical for epithelial-specific splicing of many other genes in addition to FGFR2. Several of the proteins made from these RNAs also have different functions that either help cells to stay attached in place or to promote local invasion of cancer cells that are capable of traveling to distant sites. The team is also engineering mice in which the genes for ESRP1 and 2 can be selectively “knocked-out” so that they can further study the importance of these two proteins during development as well as in disease. In addition, studies are planned to use the same splicing reporter system to screen for drugs that might restore the epithelial pathway and interfere with metastasis and fibrosis.

This work was supported by the Pennsylvania Department of Health, the National Cancer Institute, the Department of Defense, and the Penn Genome Frontiers Institute. Additional team members included Behnam Nabet in the Carstens lab and Trey K. Sato from the Hogenesch lab.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Studies and Analyses:

nachricht Real-time feedback helps save energy and water
08.02.2017 | Otto-Friedrich-Universität Bamberg

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

From rocks in Colorado, evidence of a 'chaotic solar system'

23.02.2017 | Physics and Astronomy

'Quartz' crystals at the Earth's core power its magnetic field

23.02.2017 | Earth Sciences

Antimicrobial substances identified in Komodo dragon blood

23.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>