Washington, April 22 (ANI): Researchers analyzing gene expression data from 22 tumor types have 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 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.
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. We still lack a complete understanding of their usage, regulation, and reprogramming in cancer," said Dennis Vitkup, PhD, associate professor of biomedical informatics (in the Initiative in Systems Biology) at CUMC, the study's lead investigator.
"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.
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.
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.
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.
"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.
Targeting metabolism may be a way to strike cancer at its roots, the researchers said.
The study was published today in the online edition of Nature Biotechnology. (ANI)
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