Cancer Cells: The Epitome of Greed

         Regulatory networks exist within cells to control behaviors that may potentially become pathogenic, such as migration and division. When these systems are defective, cancer cells arise and wreak havoc in an organism.  Cancer cells have broken free of regulatory constraints to divide uncontrollably and compete with normal cells for nutrients, interfering with tissue function and leading to organ failure. Cancer cells are a unique challenge for treatment because they can evade detection by the immune system, and their elimination can have deleterious effects on neighboring normal cells.

         Over several decades, researchers have studied methods to halt cancer cell growth. One facet of cancer cell physiology was highlighted in the 1920s when Otto Warburg, a German biochemist, noticed that cancer cells consumed significantly more glucose than normal cells. In order for cells to carry out the processes required for life, they must consume and dissemble glucose in a series of steps to extract energy. Increased metabolism in cancer cells indicated to Warburg that the abnormal division rate of cancer cells was driven by their insatiable need for glucose. Fifty years later, attention shifted to genetic alterations that were conducive to cancer progression, and researchers at that time believed that Warburg's observation was a consequence rather than a causative agent of cancer.

         However, the spotlight has once again turned to the metabolic properties of cancer cells due to a recent discovery described in Nature. This report states that cancer cells are highly dependent on a mutation within the enzyme called isocitrate dehydrogenase 2, or IDH2. This enzyme is a component of the citric acid cycle, which facilitates the generation of adenosine triphosphate (ATP), the main energy source in cells. Mutations within this enzyme are significant because they are hypothesized to re-route the metabolic process by favoring a faster, less efficient method of producing ATP in cancer cells. In light of this result, a drug called AG-221 was developed to combat the activity of the abnormal version of IDH2 in cancer cells. Clinical trials for AG-221 have shown great promise in acute myeloid leukemia (AML) patients, raising the possibility that the reliance of cancer cells on particular metabolic pathways can provide drug targets for cancer treatment.

       Metabolism has become a hot topic in the realm of cancer biology because it is a feature of all cells. Every cell in the body must incorporate glucose for ATP production, but cancer cells take advantage of this process to support their constant growth and proliferation. The identification of compounds that block the utilization of alternative metabolic pathways in cancer cells can serve as an innovative method of combating cancer's devastating effects. Nonetheless, more research is needed to ensure that these compounds have a minimal effect on healthy tissue and that these compounds are not a short-term fix. Cancer cells notoriously accumulate additional genetic mutations to circumvent cancer therapies, and this has hampered the formulation of effective anti-cancer drugs. Despite the uncertainties that remain, this new finding sets the stage for a greater emphasis on differential requirements between cancer cells and their normal counterparts, which will increase our knowledge of the aberrations that surface when a normal cell becomes cancerous.

Leukemia cells take advantage of metabolic pathways to support their high division rate.
Courtesy: Charles Hess, MD and Lindsey Krstic, BA; University of Virginia