While normal astrocytes generally do not dedifferentiate in response to injury, aberrant lineage plasticity is a hallmark of gliomas. These tumors typically arise from neural stem cells, but recent work has shown that astrocytes can exhibit stem cell behavior again after injury, challenging the notion that these cells are less likely to become cancerous.
The role of glioma-related genes in controlling astrocyte plasticity in the normal brain is not yet clear. It is also unclear how disruptions in these genes might interact with injury-induced changes that promote dedifferentiation, which is relevant to glioma progression and recurrence. One gene of interest in this context is p53, which inhibits somatic cell reprogramming and is commonly inactivated in glioma.
Now, researchers from the UCL Cancer Institute in London have identified a potential mechanism to explain this link, which involves genetic mutations and brain tissue inflammation working together to change cell behavior and increase the likelihood of cancer. The findings were published in the journal Current Biology (2023; https://doi.org/10.1016/j.cub.2023.02.013).
Study Details
Led by Simona Parrinello, PhD, Professor of Neuro-Oncology, and her team from the UCL Cancer Institute, the researchers used a pre-clinical mouse model to study the role of p53 in the fate of astrocytes. Specifically, they aimed to determine whether p53 loss, a common mutation in glioma, would make astrocytes more likely to form gliomas following brain injury.
The team induced brain injury in young adult mice and labeled astrocytes in red. They then knocked out the function of the p53 gene in one group of mice and left it intact in the control group. In a second group, they knocked out the p53 gene without inducing injury. The investigators discovered that the loss of p53 destabilized the identity of astrocytes in the context of a stab wound injury, making them more likely to dedifferentiate and form tumors later in life. This was due to persistent and age-exacerbated neuroinflammation at the injury site and the activation of EGFR in periwound astrocytes.
"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 become more rounded. They weren't quite stem cell-like, but something had changed," Parrinello noted. "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." Parrinello is senior author, as well as Head of the Samantha Dickson Brain Cancer Unit and co-lead of the Cancer Research UK Brain Tumour Centre of Excellence.
Additionally, the team identified EGFR as the main receiver of dedifferentiative inflammatory signals, suggesting that it acts as a rheostat in the control of astrocyte fate. However, they found that p53 loss together with cell-extrinsic EGFR activation creates the "perfect storm" for subverting the astrocyte lineage barrier and promoting tumorigenesis. The researchers' analysis of datasets from other studies supported their findings, suggesting that p53 may function as a barrier to injury-induced astrocyte dedifferentiation.
"We know that normal tissues carry many mutations which seem to just sit there and not have any major effects," Parrinello noted. "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 aging, 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."
Next, the investigators analyzed electronic medical records of over 23,000 patients who had experienced head injuries, comparing their rates of brain cancer with a control group of over 194,000 people matched for age, sex, and socioeconomic status. They used various risk factors, including known glioma risk factors, as positive and negative controls to ensure the validity of their findings. Patients who had suffered a head injury were almost 4 times more likely to develop brain cancer later in life than those who had not had a head injury (HR: 3.78, CI: 2.85-5.02, P<0.0001). The research indicates that injury may be a significant risk factor for brain cancer.
The study provides molecular insights into the mechanisms by which injury may contribute to the development of glioma, highlighting the role of p53 and EGFR in the fate of astrocytes. The findings suggest that mutations in p53 and other genes that remove barriers to injury-induced dedifferentiation may make cells more susceptible to inflammatory signals and increase the risk of tumorigenesis.
"Our research suggests that a brain trauma may contribute to an increased risk of developing brain cancer in later life," Parrinello concluded.
Dibash Kumar Das is a contributing writer.