How cancer cells make energy
More than 80 years ago, German scientist Otto Warburg claimed that he had discovered the cause of cancer – a defect in the way cells generated their energy.
Comparing normal and tumor tissues in the laboratory, Warburg showed that cancer cells are different because they make energy through a fermentation process in which sugar (glucose) converts into cellular energy without using oxygen as normal cells do. The cancer cell's less-efficient metabolic method, called glycolysis, sometimes kicks in under stressful conditions, such as long-distance running, in healthy people.
But the so-called "Warburg hypothesis" of cancer fell by the wayside; among other things, Warburg couldn't explain how cancer cells gained an advantage through glycolysis. The modern model of cancer blames the disease on damaged genes, not a metabolic defect, and most scientists today believe the latter is a result of cancer, not its trigger. One modern cancer diagnostic tool, though, exploits the metabolic difference in cancer cells. Positron emission tomography (PET) scanning detects active cancer cells in the body by their voracious appetite for glucose.
This was not the story's end, however. In the past decade, scientists have discovered unexpected connections between cancer genes and energy metabolism. Dana-Farber researcher Nika Danial, PhD, for example, has found an intimate link between glycolysis, the metabolic pathway that cancer cells use to make energy, and proteins that allow cancer cells to escape apoptosis – the normal self-destruct mechanism that eliminates damaged cells.
"Metabolism started creeping back in vogue in the 1990s," explains Matthew Vander Heiden, MD, PhD, an instructor in the genitourinary oncology group at Dana-Farber and a postdoctoral researcher working with Lewis Cantley, PhD, at Beth Israel Deaconess Medical Center.
Work by Vander Heiden and a graduate student in the Cantley lab has recently uncovered a previously unknown "switch" that, when activated by growth signals, turns on glycolysis in cancer cells. "There are two forms of a protein called pyruvate kinase – an embryonic version and an adult version," says Vander Heiden. Cancer cells use the embryonic form, which can be regulated by these growth signals to activate their abnormal way of making energy through glycolysis.
"I think this might be the key to discovering what selective advantage the Warburg effect gives to cancer cells," Vander Heiden adds. Because the pyruvate kinase step is specific to cancer cells, he and his colleagues are exploring the use of chemical inhibitors to block it as a form of therapy.
"We haven't yet found any kind of tumor that doesn't have this altered metabolism," he points out, suggesting that the kinase-blocking strategy could be widely effective.
