Resume: Traumatic brain injury may increase the risk of developing brain cancer with a glioma later in life, researchers report. The study found that brain injury caused specific genetic mutations to go along with inflammation, making brain cells more likely to become cancerous.
Source: UCL
Researchers at the UCL Cancer Institute have provided important molecular insight into how injury may contribute to the development of a relatively rare but often aggressive form of brain tumor called a glioma.
Previous studies have suggested a possible link between head injuries and increased brain tumors, but the evidence is inconclusive. The UCL team has now identified a possible mechanism to explain this link, involving genetic mutations that interact with brain tissue inflammation to alter the behavior of cells, making them more likely to become cancerous.
While this study was largely conducted in mice, it suggests that it would be important to explore the relevance of these findings to human gliomas.
The study was led by Professor Simona Parrinello (UCL Cancer Institute), head of the Samantha Dickson Brain Cancer Unit and co-lead of the Cancer Research UK Brain Tumor Center of Excellence. She said: “Our research suggests that brain trauma may contribute to an increased risk of developing brain cancer later in life.”
Gliomas are brain tumors that often originate in neural stem cells. More mature types of brain cells, such as astrocytes, are believed to be less likely to cause tumors. However, recent findings have shown that astrocytes can resume stem cell behavior after injury.
Professor Parrinello and her team therefore set out to investigate whether this property could enable astrocytes to form a tumor after brain trauma using a preclinical mouse model.
Young adult mice with brain damage were injected with a substance that permanently red-labeled astrocytes and knocked out the function of a gene called p53, known to play a vital role in suppressing many different cancers. A control group was treated in the same way, but the p53 gene remained intact. A second group of mice was subjected to p53 inactivation in the absence of injury.
Professor Parrinello said: “Normally, astrocytes are highly branched – they take their name from stars – but what we found was that without p53 and only after an injury had the astrocytes retracted their branches and become rounder. They were not 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.
This suggested to Professor Parrinello and his team that mutations in certain genes worked synergistically with brain inflammation, which is caused by acute injury and then increases over time during the natural aging process, making astrocytes more likely to initiate cancer. This process of change to stem cell-like behavior even accelerated when they injected mice with a solution known to cause inflammation.
The team then looked for evidence to support their hypothesis in human populations. In collaboration with dr. Alvina Lai of UCL’s Institute of Health Informatics, they consulted electronic health records of more than 20,000 people diagnosed with a head injury, comparing the rate of brain cancer with a control group matched by age, gender and socioeconomic status. .
They found that patients who suffered a head injury were almost four times more likely to develop brain cancer later in life than those who did not have a head injury. It’s important to keep in mind that the risk of developing brain cancer is generally low, estimated at less than 1% over a lifetime, so even after an injury the risk remains modest.
Professor Parrinello said: “We know that normal tissues contain many mutations that seem to sit there and don’t have major effects. Our findings suggest that if an injury occurs on top of those mutations, it creates a synergistic effect.
“In young brains, basal inflammation is low, so the mutations appear to be controlled even after severe brain injury. However, with age, our mouse work suggests that inflammation throughout the brain increases, but more intensely at the site of the prior injury. This may reach a certain threshold after which the mutation will now begin to manifest.”
The study is published in the journal Current Biology and involved researchers from the UCL Cancer Institute, UCL Laboratory for Molecular Cell Biology and UCL Institute of Health Informatics along with external collaborators from Imperial College London.
About this news about TBI and brain cancer research
Author: Chris Lane
Source: UCL
Contact: Chris Lane – UCL
Image: The image is in the public domain
Also see
Original research: Open access.
“Injury stimulates mutation-carrying astrocytes for dedifferentiation in later life” by Simona Parrinello et al. Current Biology
Abstract
Injury stimulates mutation-carrying astrocytes for dedifferentiation in later life
Highlights
- The tumor suppressor p53 limits the injury-induced plasticity of cortical astrocytes
- p53 loss destabilizes astrocyte identity in the context of early life injury
- Increased neuroinflammation at the site of injury leads to dedifferentiation in aging
- EGFR activation by injury signals mediates dedifferentiation downstream of p53 loss
Resume
Despite their latent neurogenic potential, most normal parenchymal astrocytes fail to dedifferentiate into neural stem cells in response to injury. In contrast, aberrant lineage plasticity is a hallmark of gliomas, and this suggests that tumor suppressors may limit astrocyte differentiation.
Here we show that p53, one of the most inactivated tumor suppressors in glioma, is a gatekeeper of astrocyte fate. In the context of stab wound injury, the loss of p53 destabilized astrocyte identity, preparing them to dedifferentiate later in life.
This was due to persistent and age-exacerbated neuroinflammation at the injury site and EGFR activation in periwound astrocytes. Mechanistically, dedifferentiation was driven by the synergistic upregulation of mTOR signaling downstream of p53 loss and EGFR, which restores stamness programs via increased translation of neurological transcription factors.
Thus, our findings suggest that first-hit mutations remove the barriers to injury-induced dedifferentiation by sensitizing somatic cells to inflammatory signals, with implications for tumorigenesis.