Cancer Prevention with Aspirin in the Ageing Gut

Within the Wellcome Centre for Mitochondrial Research at Newcastle University, the research team led by Dr Laura Greaves use intestinal organoids to investigate the role of mtDNA mutations in colorectal cancer development.  The team are also using this expertise to explore the use of aspirin as a way to reduce the risk of colorectal cancer in the ageing gut. Here, PhD student Steph Nicholson tells us more.

Colorectal cancer remains the second most common cause of cancer death in the UK despite improvements in diagnosis and treatment options, so prevention is increasingly important. Many studies have shown that aspirin reduces the risk of colorectal cancer, but when treatment is started for the first time in patients over the age of 70 there is significant risk of severe side effects including damage to the stomach lining and internal bleeding. Increased understanding of how aspirin acts on the gut and why it is less tolerated by the ageing stomach could allow its use to prevent colorectal cancer whilst avoiding harm.

The stomach and gut are covered in a protective lining that allows food to be digested and used by the body, whilst acting as a barrier against waste and harmful bacteria. During ageing, the stomach and gut become more vulnerable and are less able to repair any damage, so this protective lining breaks down. Unrepaired damage to DNA in the gut allows mutations to occur in genes that look after important stages in the life cycle of cells. These mutations happen in a specific order in the gut, beginning with the APC gene that usually protects against cancer by controlling how quickly cells can divide and grow. Many studies have shown that aspirin can also control this cell growth, preventing the development of colorectal cancer by acting against the problems caused by the APC mutation and stopping mutations in other genes from happening.

It has been suggested that sharp solid aspirin crystals wear through the gut wall, breaking down the protective layer that should shield the stomach against its own acid and digestive enzymes. To prevent this, a new soluble liquid aspirin has been developed. It can last longer in the body but has less contact with the gut wall, so it may be able to produce the same anti-cancer effect at much lower doses than traditional solid aspirin. To determine whether this soluble liquid aspirin is a safer and more effective aspirin formulation for colorectal cancer prevention in the ageing gut, we need to know why aspirin-related gastric bleeding and cancer risk increases with age, whether this soluble liquid aspirin has any different effects to traditional solid aspirin on the ageing gut and what is happening in the body to cause this. To answer these questions, the effects of traditional solid aspirin and soluble liquid aspirin are investigated using organoids. These are 3-dimensional structures that closely resemble the stomach and gut, grown from stem cells in a tissue culture dish. Aspirin treatments can then be compared safely, and any differences in how the stomach and gut respond to the aspirin can be detected by measuring changes in the amounts of specific proteins involved in key cell functions.

Steph’s PhD project is funded by The Barbour Foundation which was set up to support charities and good causes primarily in the North East of England and support research into the causes of chronic illness.