A team from University College London, UK, has unveiled a key mechanism to explain how head injuries may lead to a relatively rare but often very aggressive type of brain cancer called a glioma, according to a study published in the scientific journal Current Biology.
Previous studies have suggested a possible link, but the evidence has been largely inconclusive. The UCL team now has identified a mechanism to explain this link, where genetic mutations play a role combined with brain tissue inflammation. Overall, this changes the behaviour of nerve cells and makes them more likely to become cancerous. This study was mostly carried out in mice, but the results suggest it’s worthy of further investigation.
“Our research suggests that a brain trauma may contribute to an increased risk of developing brain cancer in later life,” said Professor Simona Parrinello (UCL Cancer Institute), Head of the Samantha Dickson Brain Cancer Unit and co-lead of the Cancer Research UK Brain Tumour Centre of Excellence.
Gliomas often start in neural stem cells. In contrast, astrocytes — which are more mature types of brain cells — are less likely to give rise to these tumours. However, recent studies suggest that astrocytes return to neural behaviours after a head injury. The UCL team decided to investigate whether these changes would make them more likely to form a glioma.
Young adult mice with a brain injury were injected with a substance to label astrocytes in red and block the function of a gene called p53, which is known to suppress different types of cancers. “Normally astrocytes are highly branched – they take their name from stars – but what we found was that without p53 and only after an injury, the astrocytes had retracted their branches and became more rounded. They weren’t quite stem cell-like, but something had changed. So we let the mice age, then looked at the cells again and saw that they had completely reverted to a stem-like state with markers of early glioma cells that could divide,” said Professor Parinello. This seems to suggest that mutations in certain genes combined with brain inflammation caused by concussion make astrocytes more likely to form a glioma.
The team wanted to find out if the same was true in humans. Working with Dr. Alvina Lai in UCL’s Institute of Health Informatics, they analysed medical records of over 20,000 people who had suffered a head injury and compared the rate of brain cancer with a control group (with no head injuries), matched for age, sex, and socioeconomic status. It turned out that patients who experienced a head injury are four times more likely to develop brain cancer later in life compared to those with no head injury. It’s important to note that the risk of developing brain cancer is low, so even after a head injury, the risk remains relatively modest.
“We know that normal tissues carry many mutations which seem to just sit there and not have any major effects. Our findings suggest that if, on top of those mutations, an injury occurs, it creates a synergistic effect. In a young brain, basal inflammation is low, so the mutations seem to be kept in check even after a serious brain injury. However, upon ageing, our mouse work suggests that inflammation increases throughout the brain but more intensely at the site of the earlier injury. This may reach a certain threshold after which the mutation now begins to manifest itself,” said Professor Parrinello.
Ragdale H, Clemens M, Tang W et al. (2023) Injury primes mutation-bearing astrocytes for dedifferentiation in later life. Current Biology, https://doi.org/10.1016/j.cub.2023.02.013