A mechanism that explains how head injury could be a risk factor for a rare brain tumour has been revealed by British researchers.
Researchers from the UCL Cancer Institute, UK, believe it is due to genetic mutations working with brain tissue inflammation to change the behaviour of cells, making them more likely to become cancerous.
Writing in Current Biology, the authors say although this study was largely carried out in mice, it is important to explore the relevance of these findings to human gliomas, which are tumours that often arise in neural stem cells.
Although more mature brain cells, such as astrocytes, have been considered less likely to give rise to tumours, recent studies have shown astrocytes can exhibit stem cell behaviour again after injury.
Study lead author Professor Simona Parrinello and her team investigated in a pre-clinical mouse study to see if this property may make astrocytes able to form a tumour following brain trauma.
Young adult mice with brain injury were injected with a substance that permanently labelled astrocytes in red and knocked out the function of the p53 gene, which has a vital role in suppressing many cancers.
In a control group, mice were treated in the same way but their p53 gene was left intact. A second group of mice was subjected to p53 inactivation in the absence of injury.
Professor Parrinello said: "Normally astrocytes are highly branched – but what we found was that without p53 and only after an injury the astrocytes had retracted their branches and become 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.”
The team believed mutations in certain genes synergised with brain inflammation, which is induced by acute injury and increases over time during the natural ageing process to make astrocytes more likely to initiate a cancer.
When they looked for evidence to support their hypothesis in human populations, they consulted electronic medical records of more than 20,000 people who had been diagnosed with head injuries, comparing the rate of brain cancer with a control group, matched for age, sex and socioeconomic status.
Patients who experienced a head injury were nearly four times more likely to develop a brain cancer later in life, than those who had no head injury. However, the team stressed the risk of developing a brain cancer is estimated at less than 1% over a lifetime, so even after an injury the risk remains modest.
“Our findings suggest that if on top of those mutations, an injury occurs, it creates a synergistic effect,” said Professor Parrinello.
“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.”
Simpson Ragdale H, Clements M, Tang W et al. Injury primes mutation bearing astrocytes for dedifferentiation in later life. Current Biology 24 February 2023.
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