Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Hundreds of alterations and potential drug targets to starve tumors identified

22.04.2013
Sweeping study of cancer metabolism identifies hundreds of alterations and potential drug targets to starve tumors

A massive study analyzing gene expression data from 22 tumor types has identified multiple metabolic expression changes associated with cancer. The analysis, conducted by researchers at Columbia University Medical Center, also identified hundreds of potential drug targets that could cut off a tumor's fuel supply or interfere with its ability to synthesize essential building blocks. The study was published today in the online edition of Nature Biotechnology.

The results should ramp up research into drugs that interfere with cancer metabolism, a field that dominated cancer research in the early 20th century and has recently undergone a renaissance. [Fuel Lines of Tumors Are New Target: http://nyti.ms/10QMkY1]

"The importance of this new study is its scope," said Dennis Vitkup, PhD, associate professor of biomedical informatics (in the Initiative in Systems Biology) at CUMC, the study's lead investigator. "So far, people have focused mainly on a few genes involved in major metabolic processes. Our study provides a comprehensive, global view of diverse metabolic alterations at the level of gene expression."

Cell metabolism is a dynamic network of reactions inside cells that process nutrients, such as glucose, to obtain energy and synthesize building blocks needed to produce new cellular components. To support uncontrolled proliferation, cancer needs to significantly reprogram and "supercharge" a cell's normal metabolic pathways.

The first researcher to notice cancer's special metabolism was German biochemist Otto Warburg, who in 1924 observed that cancer cells had a peculiar way of utilizing glucose to make energy for the cell. "Although a list of biochemical pathways in normal cells was comprehensively mapped during the last century," said Dr. Vitkup. "We still lack a complete understanding of their usage, regulation, and reprogramming in cancer."

"Right now we have something like a static road map. We know where the streets are, but we don't know how traffic flows through the streets and intersections," said Jie Hu, PhD, a postdoctoral researcher at Columbia and first author of the study. "What researchers need is something similar to Google Traffic, which shows the flow and dynamic changes in car traffic."

Drs. Hu and Vitkup's study is an important step toward achieving this dynamic view of cancer metabolism. Notably, the researchers found that the tumor-induced expression changes are significantly different across diverse tumors. Although some metabolic changes—such as an increase in nucleotide biosynthesis and glycolysis—appear to be more frequent across tumors, others, such as changes in oxidation phosphorylation, are heterogeneous.

"Our study clearly demonstrates that there are no single and universal changes in cancer metabolism," said Matthew Vander Heiden, MD, PhD, assistant professor at MIT, and a co-author of the paper. "That means that to understand transformation in cancer metabolism, researchers will need to consider how different tumor types adapt their metabolism to meet their specific needs."

The researchers also found that expression changes can mimic or cooperate with cancer mutations to drive tumor formation. A notable example is the enzyme isocitrate dehydrogenase. In several cancers, such as glioblastoma and acute myeloid leukemia, mutations in this enzyme are known to produce a specific metabolite—2-hydroxyglutarate—that promotes tumor growth. The Columbia team found that isocitrate dehydrogenase expression significantly increases in tumors with the recurrent mutations. Such an overexpression may create an efficient enzymatic factory for overproduction of 2-hydroxyglutarate.

The analysis also led the researchers to an interesting finding in colon cancer. In several other cancers, mutations in two enzymes—succinate dehydrogenase and fumarate hydratase—can promote tumor formation as a result of efflux from mitochondria and accumulation of their substrates, fumarate and succinate. The researchers found that in colon cancer, accumulation of these metabolites may be caused by a significant decrease in the enzymes' expression. This was confirmed when metabolomics data from colon tumor patients showed significantly higher concentrations of fumarate in tumors than in normal tissue.

"These are just several examples of how cancer cells use various creative mechanisms to hijack the metabolism of native cells for their own purposes," said Dr. Vitkup.

For cancer researchers looking for new drug targets, Dr. Vitkup's team also found hundreds of differences between normal and cancer cells' use of isoenzymes. This opens up additional possibilities for turning off cancer's fuel and supply lines. Isoenzymes often catalyze the same reactions, but have different kinetic properties: Some act quickly and sustain rapid growth, while others are more sluggish. In kidney and liver cancers, for example, a quick-acting aldolase isoenzyme—suitable for fast cell proliferation—was found to be more prevalent than the more typical slow-moving version found in normal kidney and liver tissue. Although a few examples of differential isoenzyme expression in tumors were already known, the Columbia researchers identified hundreds of isoenzymes with cancer-specific expression patterns.

"Inhibiting specific isoenzymes in tumors may be a way to selectively hit cancer cells without affecting normal cells, which could get by with other isoenzymes," said Dr. Hu.

In fact, a recent study from Matthew Vander Heiden's laboratory demonstrated the potential of targeting a specific isoenzyme, pyruvate kinase M2, expression of which often increases in tumors. "The comprehensive expression analysis suggests that a similar approach could potentially be applied in multiple other cases," said Dr. Vander Heiden.

Targeting metabolism may be a way to strike cancer at its roots. "Cancer cells usually have multiple ways to turn on their growth program," said Dr. Vitkup. "You can knock out one, but the cells will usually find another pathway to turn on proliferation. Targeting metabolism may be more powerful, because if you starve a cell of energy or materials, it has nowhere to go."

The paper is titled, "Heterogeneity of tumor-induced gene expression changes in the human metabolic network." The other authors are Jason W. Locasale (Cornell University), Jason H. Bielas (Fred Hutchinson Cancer Research Center, Seattle, Wash.; and University of Washington, Seattle, Wash.), Jacintha O'Sullivan (St. Vincent's University Hospital, Dublin, Ireland), Kieran Sheahan St. Vincent's University Hospital, Dublin, Ireland), and Lewis C. Cantley (Harvard Medical School).

Dr. Vander Heiden is a consultant and advisory board member, and Dr. Cantley is a consultant and founder, of Agios Pharmaceuticals. The authors report no other financial or potential conflicts of interest.

This work was supported by National Institutes of Health grant GM079759 to Dr. Vitkup and National Centers for Biomedical Computing grant U54CA121852 to Columbia University. Dr. Locasale is supported by an NIH Pathway to Independence Award R00CA168997. Dr. Bielas is supported by an Ellison Medical Foundation New Scholar award AG-NS-0577-09, a National Institute of Environmental Health Sciences grant R01ES019319, and New Development Funds from the Fred Hutchinson Cancer Research Center. Dr. Vander Heiden acknowledges support from the Burroughs Wellcome Fund, the Damon Runyon Cancer Research Foundation, the Smith Family, and the National Cancer Institute.

Columbia University Medical Center provides international leadership in basic, pre-clinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

Karin Eskenazi | EurekAlert!
Further information:
http://www.cumc.columbia.edu

More articles from Life Sciences:

nachricht Inactivate vaccines faster and more effectively using electron beams
23.03.2017 | Fraunhofer-Institut für Organische Elektronik, Elektronenstrahl- und Plasmatechnik FEP

nachricht Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>