Cancer metabolism 101
“Feed me!” Cancer is caused by the uncontrolled proliferation of cells. Their rapid growth comes with a voracious appetite to support their nutritional demands. To satisfy these demands, cancer cells rewire their metabolism. Increasingly, scientists are looking to exploit the metabolic differences between normal and cancer cells for the development of new anti-cancer therapies.
The altered metabolism of cancer cells includes an increased demand for glucose (a simple sugar) and glutamine (an amino acid). But cancer cells don’t metabolize glucose like normal cells. They use an anaerobic pathway that’s less efficient at generating ATP compared to the alternative aerobic pathway. Therefore, a higher rate of glucose uptake is required to meet the increased demand needed to support rapid tumor progression.
Cancer has its own metabolism In all cells glucose is broken down into pyruvate. In normal cells, most pyruvate enters the Krebs cycle (citric acid cycle) in mitochondria—the factories in the cell that produce ATP. In cancer cells, pyruvate is converted to lactate in a process termed “aerobic glycolysis” also known as the Warburg Effect—a hallmark of tumor cells. It’s a less efficient way of generating energy, and scientists are not entirely clear why tumor cells use this way to extract energy from glucose.
But the differences don’t stop there. Cancer cells undergo a shift from catabolic (breaking down molecules) to anabolic (building molecules) metabolism to produce the extra protein, nucleic acids, and lipids they need to support their accelerated rate of proliferation. They also take up amino acids, and glutamine is particularly important. It acts as a key source of nitrogen, which is required for new nucleotide and amino acid synthesis, and a source of carbon, to replenish Krebs cycle intermediates and to produce more pyruvate. In fact, some tumors are so addicted to glutamine, they will stop growing and die without it.
Targeting tumor-cell metabolism
During the past decade, targeting cancer metabolism has emerged as a promising therapy. The approach has led to drugs in development that interfere with glycolysis, the Krebs cycle, glutamine metabolism, lipid biosynthesis, and other pathways that tumor cells overuse compared to normal cells. The rationale is that cancer cells will be more susceptible to interruptions in these avenues since they are using them at a higher rate than normal cells.
Tumor-cell targeting gets more complex when one considers that tumors not only contain malignant cells but also non-transformed stromal, endothelial, and immune cells. In fact, cancer cells can modulate their microenvironment to serve their own needs.
For example, white blood cells (leukocytes) can respond to tumor-derived signals by creating an immunosuppressive environment that actually enables tumors to hide from the immune system. Additionally, stromal cells (fibroblasts, endothelial cells, and hematopoietic-derived cells) can contribute to tumor growth by sending stimulating pro-survival, death-prevention, and chemoresistance signals. Because of their fundamental role in tumor development and growth, scientists and clinicians are starting to target multiple signaling pathways between the tumor and stromal cells that will lead to more-effective cancer treatments.
As researchers learn more about how cancer cells rewire themselves and their environment to support an excessive uptake of nutrients, they are creating a lens to study cancer in a way that we may learn to starve tumors to death.
To learn more about Sanford-Burnham research on cancer metabolism, see these stories: