The work celebrated with the 2019 Nobel Prize in Physiology or Medicine will lead the way for promising new strategies to fight cancer. William Kaelin, Sir Peter Ratcliffe and Gregg Semenza have been awarded the prize for their discoveries of how cells sense and adapt to oxygen levels. These three scientists identified the molecular pathway that regulates the response of cells to changing levels of oxygen, allowing for the understanding of how a reduction in oxygen levels affects energy production.
In animals, oxygen is used by cells to turn the energy from the food we eat into useful energy that the cell can use, so evolutionary mechanisms have ensured that there is an efficient method to supply oxygen to organs throughout the body. During exercise your muscles require more energy, resulting in a reduction of oxygen in the muscles as it is used up by the cells faster. You know that uncomfortable burning feeling you get during a really hard work-out? That is because of a build-up in lactic acid. Because there isn’t enough oxygen, the cells use oxygen-independent pathways to produce energy that produces lactic acid as a waste product. Once you finish exercising you continue to breathe quickly for a little while, this extra oxygen you breathe in breaks down the lactic acid, your cells can return to using oxygen-dependent energy formation and the cramps begin to fade. Just like your muscles during exercise, solid tumours are deprived of adequate oxygen supplies. In this case, the rapid increase in the number of cells in a tumour reduces the ability of oxygen to reach the cells at the centre.
When oxygen levels are reduced, which is referred to as hypoxia, cells react by triggering the ‘hypoxic response’. It has been shown that as oxygen levels fall, there is an increase in the hormone erythropoietin (EPO). This increase in EPO results in the formation of new blood vessels and an increase in the number of red blood cells, which carries oxygen around the body. In fact, Lance Armstrong used EPO as a performance enhancing drug to increase oxygen delivery to the muscles, resulting in him being stripped of several Tour de France titles once discovered. An increase in EPO activates the hypoxic response by increasing the expression of a family of proteins called Hypoxia-Inducible Factors (HIF). HIF is extremely important in the body’s response to low oxygen concentrations but is even more important in cancer cells.
Cancer is caused by the accumulation of mutations in the genetic sequence that allows cells to continually grow and divide. Some of these mutations can result in HIF being active all the time. In your muscle cells, where HIF is not mutated, HIF activity is turned off when oxygen levels return to normal following exercise. This is what allows your cells return to using oxygen-dependent energy formation and relieves your sore muscles. However, in some cancers were HIF remains continuously active, HIF contributes to the survival of cells within a tumour by modifying the energy production so that it can continuously occur in an oxygen-independent manner. This contributes to the progression of the cancer.
EPO is now being considered as a potential target to fight off cancer cells, by blocking this oxygen sensing machinery and starving the tumour of nutrients. The vast number of mutations that can occur in cancer cells means it is essential for continued discovery of new potential therapeutics that exploit these genetic vulnerabilities.