Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers pinpoint 2 genes that trigger severest form of ovarian cancer

27.01.2015

UNC geneticists create the first mouse model of ovarian clear cell carcinoma; show how a known drug can suppress tumor growth

In the battle against ovarian cancer, UNC School of Medicine researchers have created the first mouse model of the worst form of the disease and found a potential route to better treatments and much-needed diagnostic screens.


Clumps of ovarian clear cell carcinoma cells formed when the two genes ARID1A and PIK3CA were mutated in mice.

Credit: Ron Chandler, Ph.D., UNC School of Medicine

Led by Terry Magnuson, PhD, the Sarah Graham Kenan Professor and chair of the department of genetics, a team of UNC genetics researchers discovered how two genes interact to trigger cancer and then spur on its development.

"It's an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women," said Magnuson, who is also a member of the UNC Lineberger Comprehensive Cancer Center. Not all mouse models of human diseases provide accurate depictions of the human condition. Magnuson's mouse model, though, is based on genetic mutations found in human cancer samples.

Mutations in two genes -ARID1A and PIK3CA - were previously unknown to cause cancer. "When ARID1A is less active than normal and PIK3CA is overactive," Magnuson said, "the result is ovarian clear cell carcinoma 100 percent of the time in our model."

The research also showed that a drug called BKM120, which suppresses PI3 kinases, directly inhibited tumor growth and significantly prolonged the lives of mice. The drug is currently being tested in human clinical trials for other forms of cancer.

The work, published today in the journal Nature Communications, was spearheaded by Ron Chandler, PhD, a postdoctoral fellow in Magnuson's lab. Chandler had been studying the ARID1A gene - which normally functions as a tumor suppressor in people - when results from cancer genome sequencing projects showed that the ARID1A gene was highly mutated in several types of tumors, including ovarian clear cell carcinoma. Chandler began researching the gene's precise function in that disease and found that deleting it in mice did not cause tumor formation or tumor growth.

"We found that the mice needed an additional mutation in the PIK3CA gene, which acts like a catalyst of a cellular pathway important for cell growth," Chandler said. Proper cell cycle regulation is crucial for normal cell growth. When it goes awry, cells can turn cancerous.

"Our research shows why we see mutations of both ARID1A and PIK3CA in various cancers, such as endometrial and gastric cancers," Chandler said. "Too little expression of ARID1A and too much expression of PIK3CA is the perfect storm; the mice always get ovarian clear cell carcinoma. This pair of genes is really important for tumorigenesis."

Magnuson's team also found that ARID1A and PIC3CA mutations led to the overproduction of Interleukin-6, or IL-6, which is a cytokine - a kind of protein crucial for cell signaling that triggers inflammation. "We don't know if inflammation causes ovarian clear cell carcinoma, but we do know it's important for tumor cell growth," Chandler said.

Magnuson added, "We think that IL-6 contributes to ovarian clear cell carcinoma and could lead to death. You really don't want this cytokine circulating in your body."

Magnuson added that treating tumor cells with an IL-6 antibody suppressed cell growth, which is why reducing IL-6 levels could help patients.

Although this research is necessary to find better cancer treatments, Magnuson and Chandler say that their finding could open the door to better screening tools.

"If we can find something measurable that's downstream of ARID1A - such as a cell surface protein or something else we could tease apart - then we could use it as a biomarker of disease," Chandler said. "We could create a way to screen women. Right now, by the time women find out they have ovarian clear cell carcinoma, it's usually too late. If we can find it earlier, we'll have much better luck successfully treating patients."

###

The National Institutes of Health funded this research. Dr. Chandler was supported by a Postdoctoral Fellowship from the American Cancer Society and an Ann Schreiber Mentored Investigator Award (258831) from the Ovarian Cancer Research Fund.

Other co-authors, all at UNC, are William Kim, MD, associate professor of medicine and genetics; Fernando Pardo-Manuel de Villena, PhD, professor of genetics and associate chair for research; Jonathan Schisler, PhD, research assistant professor of pharmacology; Joshua Starmer, PhD, research assistant professor of genetics; Matthew Wilkerson, PhD, research assistant professor of genetics; Jesse Raab, PhD, postdoctoral fellow in genetics, graduate students John Didion and Daniel Serber; research technician Jessie Xiong; Magnuson lab manager Della Yee; and David Darr, operations director of UNC's Mouse Phase 1 Unit.

Duke University postdoctoral fellow Jeffrey Damrauer, PhD, was also a co-author; he was a graduate student in the Kim lab during this study. Schisler is a member of the McAllister Heart Institute. Kim and Pardo-Manuel de Villena are members of the UNC Lineberger Comprehensive Cancer Center.

Mark Derewicz | EurekAlert!

Further reports about: ARID1A PIK3CA carcinoma cell carcinoma cell growth genes ovarian ovarian cancer

More articles from Life Sciences:

nachricht Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)

nachricht CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

New Study Will Help Find the Best Locations for Thermal Power Stations in Iceland

19.01.2017 | Earth Sciences

Not of Divided Mind

19.01.2017 | Life Sciences

Molecule flash mob

19.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>