Highlights in this article
Cancer cells are thought to have increased metabolism to support their uncontrolled growth. Using a novel technique, Dr. Rabinowitz’s group demonstrated that solid tumors produce energy at a slower than normal rate instead of being hypermetabolic in mice harboring tumors. This indicates that cancer cells save energy to support uncontrolled growth. Targeting metabolism is currently one of the strategies to combat cancers because we thought cancer cells are hypermetabolic. However, the results of clinical trials targeting cancer metabolism are disappointing. This research article might explain why clinical trials targeting cancer metabolism do not work and might show smart strategies for cancer cells to grow in the body.
Background
Tissues produce energy called ATP in two ways- glycolysis and the TCA cycle coupled to the electron transport chain in the presence of oxygen. The Warburg effect is a phenomenon observed in cancer cells in which their metabolism is shifted away from normal oxidative phosphorylation (TCA cycle) and towards anaerobic glycolysis, even in the presence of oxygen. This shift results in the production of lactic acid, which can be used by cancer cells for energy and growth. Recent research has suggested that the Warburg effect is the result of genetic and epigenetic alterations in cancer cells, and may be linked to other factors such as hypoxia and nutrient availability.
Cancer metabolism is the study of how cancer cells use energy and nutrients to enable their growth and proliferation. The rationale to target cancer metabolism is to exploit the differences between the metabolic pathways of normal cells and cancer cells in order to slow or stop cancer cell growth and proliferation. Cancer cells have been found to use a different set of metabolic pathways, such as the Warburg effect (see above), which allows them to generate energy and grow faster than normal cells. By targeting these pathways, researchers are hoping to find new treatments that can stop or slow the growth of cancer cells, while leaving normal cells unaffected. Additionally, targeting metabolic pathways may also help to identify new drug targets or biomarkers to aid in the early detection and diagnosis of cancer.
However, the absolute rate of these pathways in tumors remains unclear.
Discovery
Dr. Rabinowitz’s lab explores the relationship between energy production and growth in solid tumors. To do this, they measure the rates of glycolysis and the tricarboxylic acid (TCA) cycle in healthy mouse tissues, Kras-mutant solid tumors, metastases and leukemia, and then calculate total ATP synthesis rates. They found that TCA cycle flux is suppressed in all five primary solid tumor models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumors using a new method they developed. As expected, glycolysis flux is increased in tumors compared with healthy tissues (the Warburg effect), but this glycolysis increase is insufficient to compensate for low TCA flux in terms of ATP production. Their results suggest that, instead of being hypermetabolic, as commonly assumed, solid tumors generally produce ATP at a slower than normal rate. They propose that, as solid tumors develop, cancer cells shed energetic costly tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP. Therefore, we might need to reconsider the strategies/treatments targeting cancer metabolism to conquer these complicated strategies for cancer cells.
For more information:
Nature 2023 2/1
https://www.nature.com/articles/s41586-022-05661-6
Slow TCA flux and ATP production in primary solid tumors but not metastases
Dr. Rabinowitz’s website: