Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A circuitous route to therapy resistance

27.06.2013
Gliomas are malignant brain tumors that arise from glial cells called astrocytes, found in the central nervous system.

"In treating malignant gliomas, we currently combine radiotherapy with the anticancer drug temozolomide. However, in some patients, tumors rapidly become resistant to both treatment methods," says neurooncologist Professor Dr. Michael Platten, who leads a cooperation unit of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Department of Neurooncology of Heidelberg University Hospital. "We therefore urgently need new methods of treating these diseases more effectively."

Chemotherapy and radiotherapy damage the DNA of tumor cells. Normally these DNA defects automatically trigger the cellular suicide program known as apoptosis. However, tumor cells possess an efficient DNA repair system that they use to protect themselves from the consequences of therapy, thus evading cell death.

Key repair mechanisms in the cell can only work efficiently if a molecule called NAD+ is present. When DNA repair is running at full throttle, as is the case during radiation therapy, NAD+ supplies are quickly exhausted in a cancer cell, leading to DNA damage that goes unrepaired and ultimately cell death. Cancer researchers are therefore trying to use drugs to deprive cells of NAD+ to prevent resistance to therapies. Substances that inhibit the enzyme which produces NAD+ are already being tested in clinical trials.

However, cells can produce NAD+ in a number of ways. They can synthesize it directly, or use a substance called quinolinic acid, a metabolite of the protein building-block tryptophan, as an alternative source to produce NAD+. Michael Platten and his team had discovered that malignant gliomas contain large amounts of quinolinic acid. "We wanted to know whether gliomas might use this circuitous route in order to produce enough NAD+ and thus escape therapy," says neuropathologist Felix Sahm, first author of the publication.

If direct NAD+ production is blocked, malignant glioma cells, unlike normal astrocytes, increase production of QRPT. This enzyme breaks down quinolinic acid into NAD+. Therapies involving the anticancer drug temozolomide, radiation, or oxidative stress were found to lead to increased levels of QRPT in tumors. The higher the degree of malignancy of the gliomas that were investigated, the more QRPT they contained. Brain tumors that recurred after combined radiotherapy-chemotherapy had a poorer prognosis when the cancer cells produced high levels of quinolinic acid.

The researchers also discovered that the tumor cells are not capable of forming quinolinic acid on their own. Instead, the substance is produced by immune cells called microglia, which migrate in large quantities into gliomas. Microglia cells may constitute up to 50 percent of the total cell content of a glioma.

In these cases, only the tumor cells contain QRPT; healthy astrocytes do not. Hence only the tumor cells are capable of breaking down quinolinic acid into NAD+. "The malignant transformation of astrocytes appears to be linked to their ability to use quinolinic acid as an alternative source of NAD+ and thus develop resistance against radiotherapy and chemotherapy," says Michael Platten. "A link between microglia and the malignancy of gliomas has been known for some time – now we may have found a possible cause. The key enzyme for the alternative NAD+ supply is QRPT. An agent directed against this enzyme might help suppress therapy resistance in brain cancer. This might enable us to achieve better outcomes in treating malignant brain tumors using existing methods."

Felix Sahm, Iris Oezen, Christiane A. Opitz, Bernhard Radlwimme5, Andreas von Deimling, Tilman Ahrendt, Seray Adams, Helge B. Bode, Gilles J. Guillemin, Wolfgang Wick and Michael Platten: The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress. Cancer Research 2013, DOI: 10.1158/0008-5472.CAN-12-3831

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

Dr. Sibylle Kohlstädt | EurekAlert!
Further information:
http://www.dkfz.de

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

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: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Thanks for the memory: NIST takes a deep look at memristors

22.01.2018 | Materials Sciences

Radioactivity from oil and gas wastewater persists in Pennsylvania stream sediments

22.01.2018 | Earth Sciences

Saarland University bioinformaticians compute gene sequences inherited from each parent

22.01.2018 | Life Sciences

VideoLinks Wissenschaft & Forschung
Overview of more VideoLinks >>>