Cancer Cells Use an Enzyme that Breaks Down Stored Fats to Fuel Aggressive Growth and Spread
The Bottom Line
Cancer cells appear to take advantage of an enzyme that breaks down stored fats in cells to support their aggressive growth and spread, a discovery that could lead to new cancer treatments.
The Whole Story
Researchers have long known that the metabolism of cancer cells is different in many ways from the metabolism of normal cells. However, little is known about whether and how these metabolic changes actually drive the behavior of cancer cells. In seeking answers to these questions, a group of NCI-supported scientists analyzed the activity of a group of metabolic enzymes called serine hydrolases in cancer cells grown in the laboratory that varied in their aggressiveness. They found that two serine hydrolase enzymes were consistently more active in aggressive cancer cells. Although one of these enzymes was already suspected to play a role in cancer, the other—known as monoacylglycerol lipase, or MAGL—had not been associated with cancer previously. MAGL breaks down intracellular triglyceride fats to fatty acids and glycerol.
In their research, the scientists studied aggressive and nonaggressive cancer cells from three different tumor types, including melanoma, ovarian cancer, and breast cancer. In addition, they found that MAGL activity was higher in tumor tissue from high-grade ovarian cancers compared with tissue from benign ovarian tumors or low-grade ovarian cancers.
The researchers also found that increased MAGL activity in aggressive cancer cells was associated with increased levels of free fatty acids (fatty acids not attached to other molecules), suggesting that MAGL plays a role in controlling free fatty acid levels in cancer cells. MAGL does not, in general, control free fatty acid levels in normal cells, suggesting that cancer cells co-opt, or highjack, this enzyme’s function to support their needs.
To determine whether increased MAGL activity plays a direct role in cancer cell aggressiveness, the researchers used two different methods to block the activity of this enzyme in aggressive cancer cells. The treated cancer cells showed a reduced ability to migrate and they were less invasive, both signs of reduced aggressiveness. In contrast, when the researchers used recombinant DNA techniques to introduce extra copies of the MAGL gene into nonaggressive cancer cells, the modified cells showed increased capabilities for migration and invasion, indicating increased aggressiveness. Moreover, when cells with extra copies of the MAGL gene and control cells were injected into mice and allowed to form tumors, the tumors formed by the cells with extra copies of the MAGL gene grew faster than the control tumors.
On the assumption that MAGL’s effects on cancer cell aggressiveness were mediated by free fatty acids or their breakdown products (their metabolites), the researchers then exposed nonaggressive cancer cells to free fatty acids in the laboratory. The scientists found that this treatment increased the cells’ ability to migrate. Furthermore, when mice bearing tumors formed from cancer cells in which MAGL activity was blocked were fed a high-fat diet, the tumors grew faster.
Overall, these results show that cancer cells can co-opt MAGL’s function to increase the supply of free fatty acids, which they use to support their malignant behavior. The results also suggest that a high-fat diet might promote the growth and spread of cancer cells that do not use MAGL in this manner. In addition, the findings suggest that drugs that target MAGL might someday be used for cancer therapy.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.