Putting the brakes on tumor growth

Without the ACSS2 enzyme, cancer cells would scarcely be able to divide and multiply as rapidly as they sometimes do. This enzyme enables them to use acetate, in other words acetic acid ester, instead of glucose to produce lipids and thus erect new cell walls, for example. If the enzyme is missing, the cancer cells die under certain conditions.

This discovery is now being reported by an international team of scientists in the journal Cancer Cell. According to the scientists, this discovery may provide a suitable target for a new treatment in which the tumor is “starved”, so to speak. Würzburg professor Almut Schulze is involved in the work. She has been conducting research at the University of Würzburg’s Biocenter in the Department of Biochemistry and Molecular Biology for the past year; prior to that, she worked for 16 years at Cancer Research UK’s London Research Institute.

Effective strategies to combat the lack of nourishment

In contrast to normal cells in tissues, cancer cells multiply very quickly. To do this they need sufficient nourishment to construct new cell components and gain energy. An important nutrient for cancer cells is glucose, which the organism acquires by breaking down food and distributes throughout the body in the bloodstream. However, tumors often grow so quickly that they are not supplied with sufficient blood vessels. So, they lack nutrients and oxygen, which noticeably retards their growth. Cancer cells, however, have developed strategies that enable them to continue to grow even under these conditions. Researchers are trying to identify these changes in the metabolism of cancer cells so that they can use this knowledge to find new targets for cancer treatment.

Sights set on prominent enzymes

In the study just published in the journal Cancer Cell researchers from various disciplines came together to tackle this problem from numerous angles. “First of all we simulated the metabolic processes in cancer cells on the computer and then analyzed them,” reports Almut Schulze. The scientists focused mainly on enzymes that control particularly important responses. They actually discovered a large number of enzymes that are needed for the formation of lipids.

As a next step they deliberately deactivated individual enzymes in breast cancer and prostate carcinoma cells, with the help of genetic engineering, and examined the effects on the growth of the cells. To simulate the conditions in the tumor, the cells were held in a special incubator in which the concentration of oxygen could be regulated. The burning question here: Which enzyme needs to be deactivated in order for cancer cells in a low-oxygen environment to die?

“The enzyme that had the strongest effect was ACSS2,” Almut Schulze reveals. ACSS2 enables cancer cells to switch to acetate when they are lacking glucose and to continue producing lipids in that manner. Acetate is found in small quantities in the blood and in tissues and can be absorbed and processed by tumor cells under certain conditions. As the studies by the scientists show, cancer cells absorb increased acetate and use it to produce lipids if they lack oxygen.

Growth successfully retarded in the experiment

“When the ACSS2 enzyme was deactivated, the cells were no longer able to construct sufficient cell components. As a result, the cells could no longer multiply so quickly, and tumor growth in laboratory animals could be halted,” reveals Schulze. To show that ACSS2 also plays an important role in human tumors, the researchers also examined tissue in breast cancer patients. They found that extremely advanced and aggressive tumors that often contain regions with a shortage of oxygen form large quantities of this enzyme. “If we could develop an agent that stops ACSS2 from functioning, this could be used to treat such tumors,” hopes the scientist.

Experts from many places and numerous fields

Molecular biologists, biochemists and pharmaceutical chemists, each one an expert in his or her research area, from London, Cambridge, Oxford, Glasgow, and Würzburg, were involved in the study; they were supported by the staff of a large pharmaceutical company. The team led by Almut Schulze has been looking into the role of lipid synthesis in cancer development for many years now. Its main contribution to this study was its identification of ACSS2 as an important enzyme for the growth of cancer cells and its examination of tumor tissue. In future, Schulze and her colleagues are keen to investigate any further roles that ACSS2 might play for tumor cells.

Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress. Zachary T. Schug, Barrie Peck, Dylan T. Jones, Qifeng Zhang, Shaun Grosskurth, Israt S. Alam, Louise M. Goodwin, Elizabeth Smethurst, Susan Mason, Karen Blyth, Lynn McGarry, Daniel James, Emma Shanks, Gabriela Kalna, Rebecca E. Saunders, Ming Jiang, Michael Howell, Francois Lassailly, May Zaw Thin, Bradley Spencer-Dene, Gordon Stamp, Niels J.F. van den Broek, Gillian Mackay, Vinay Bulusu, Jurre J. Kamphorst, Saverio Tardito, David Strachan, Adrian L. Harris, Eric O. Aboagye, Susan E. Critchlow, Michael J.O. Wakelam, Almut Schulze, and Eyal Gottlieb. http://dx.doi.org/10.1016/j.ccell.2014.12.002

Contact

Prof. Dr. Almut Schulze, T: +49 (0)931 31-83290, almut.schulze@uni-wuerzburg.de