Essential Process of Tumor Growth Revealed with PET

Researchers recently found that the metabolic process known as the Warburg effect is essential for tumors' rapid growth, and identifies the M2 form of pyruvate kinase (PKM2; an enzyme involved in glucose metabolism) as an important mechanism behind this process. This discovery could provide a target for the development of future cancer therapies

Nearly 80 years ago, scientists observed that cancer cells perform energy metabolism in a way that is different from normal adult cells. Many decades later, this observation was exploited by clinicians to better visualize tumors using positron emission tomography (PET) imaging technology. But it has not been known precisely how tumor cells perform this alternate metabolic task, nor was it known if this process was fundamental for tumor growth.

Now, two studies published in the March 13, 2008, issue of the journal Nature may help answer these questions. The study was led by researchers at Beth Israel Deaconess Medical Center (BIDMC; Boston, MA, USA; www.bidmc.harvard.edu) and Harvard Medical School (Cambridge, MA, USA; www.hms.harvard.edu). "With this study we have answered a fundamental question regarding the ability of tumor cells to rapidly grow and proliferate,” explained senior author Lewis Cantley, Ph.D., director of the Cancer Center at BIDMC and professor of systems biology at Harvard Medical School.

Metabolic regulation in rapidly growing tissues, such as fetal tissue or tumors, is different from that of normal adult tissue, Dr. Cantley explained. "Through aerobic glycolysis, or the Warburg effect, cancer cells produce energy by taking up glucose at much higher rates than other cells while, at the same time, using a smaller fraction of the glucose for energy production. This allows cancer cells to function more like fetal cells, promoting extremely rapid growth.”

This distinctive metabolic characteristic of cancer cells has led to the effectiveness of PET imaging as a means of cancer detection because radioactive glucose injected into patients prior to the imaging exam is preferentially taken up by glucose-hungry tumor cells, the regions of high glucose uptake are displayed significantly on the PET scan.

Using an innovative proteomic screen to identify new phosphotyrosine binding proteins, Dr. Cantley and colleagues first determined that PKM2 can bind to phosphotyrosine-containing peptides. "We observed that in contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in fetal cells, interacted with phosphotyrosine,” explained Dr. Cantley.

To understand the implications of this discovery, the investigators then embarked upon experiments to evaluate the importance of PKM2 to cancer cells. Reckoning that tumor tissue switches pyruvate kinase expression from an adult M1 isoform to the embryonic M2 isoform, they performed immunoblotting and immunohistochemistry analysis of numerous cancer cell lines, breast cancer models and human colon cancer, confirming that PKM2 was the only form of pyruvate kinase found in cancerous tissue.

The findings are consistent with the hypothesis that tumor cells preferentially use glucose for purposes other than making adenosine triphosphate (ATP), used for intracellular energy transfer.


Related Links:
Beth Israel Deaconess Medical Center
Harvard Medical School