Glioblastoma is one of the deadliest human cancers, with most patients surviving just 12 to 15 months from diagnosis. There is no treatment that is effective in the long-term.
In this project, Dr Dirk Sieger and colleagues aimed to understand how glioblastoma influences immune cells to make them promote its own growth. More specifically, Dr Sieger’s project found evidence that very small particles called extracellular vesicles play an important role during glioblastoma initiation and development by impacting on the immune cells and subsequently on glioblastoma growth. This understanding opens up promising new avenues for research that ultimately has the potential to provide significant benefits for patients with glioblastoma.
Glioblastoma is the most common primary brain cancer in adults, with around 2,500 cases diagnosed every year in the UK.
It is a grade four tumour, meaning that it grows and spreads quickly. It infiltrates the brain, wrapping finger-like tentacles around vital brain structures, making complete surgical removal impossible.
The current treatment strategy includes surgery to remove as much tumour as possible, followed by radiotherapy and chemotherapy to destroy remaining tumour. This prolongs survival but is not curative. Only a quarter of patients survive more than a year from diagnosis.
The need for new treatments is urgent.
Read more: About brain tumours
Glioblastomas are recognised by the immune cells of the brain, the ‘microglia’. Unfortunately, however, rather than fighting the brain tumours, the microglia have been shown to actively promote their growth. This is disastrous behaviour and we don’t understand why it happens.
Dr Sieger’s previous research had shown that microglia acquire this tumour promoting activity at the earliest stages of glioblastoma formation. It is not known exactly how this is happening, but Dr Sieger and his colleague Dr Mazzolini hypothesise that very small particles called extracellular vesicles (EVs) are released by the cells that initiate glioblastoma. These EVs are then taken up by microglia and change their activity. To test this hypothesis, the team used a combination of different laboratory models to understand if and how these EVs impact on the function of microglia.
Specifically, the team used a high-resolution microscope to look inside zebrafish brains to visualise the release and uptake of different types of EVs during glioblastoma initiation stages. What the team observed was that that EVs from zebrafish and human glioblastoma initiating cells are all engulfed by zebrafish microglia and affect their function in the brain. These results then allowed the team to use another zebrafish model to understand the role of EVs in the communication between glioblastoma initiating cells and microglia during the early stages of tumour growth. Finally, the team also tested different drug compounds known to interfere with EV release and assessed their efficiency and impact on the microglial population in living brains. Importantly, they showed that inhibiting EV release in the brain resulted in microglia engulfing tumour cells and impaired tumour growth. These results encouraged the team to perform further experiments to understand in detail how EVs from human glioblastoma cells change the gene expression and function of human microglia cells.
Microglia are extremely sensitive cells. They show their normal function and behaviour only in their natural environment, the brain. Hence their function cannot be studied in test tubes – only in the living brain.
Zebrafish have become powerful discovery tools for human disease in recent years. They share 71% of human genes (82% of disease-related genes), and offer superb imaging opportunities due to the transparency of the larva, allowing monitoring of biological events in real time and in situ.
This project uses larval zebrafish, at an early stage of development. Their use was reviewed as part of the application process and the team has the necessary approvals to conduct this work.
Read our policy on the use of animals
Glioblastoma is one of the most devastating forms of cancer. It has no treatment that is effective in the long-term, and most patients die within 12 to 15 months of diagnosis. New treatments are desperately needed. Since microglia play a crucial role during tumour growth and tumour invasiveness, these cells are promising targets for therapy. Understanding exactly how microglia are transformed from anti-tumour to pro-tumour is the necessary first step to find treatments to inhibit this transformation.
Dr Sieger’s project has provided evidence that extracellular vesicles play an important role during glioblastoma initiation by impacting on microglia and subsequently on glioblastoma growth. Their experiments also revealed specific changes in gene expression in microglia induced by the EVs. These results lay the groundwork for future research that can provide detailed insights on how these changes impact on glioblastoma growth and the foundation for new approaches to interfere therapeutically in this growth.
Taken together, these findings open promising avenues for research that could ultimately be translated into clinical applications, with the potential to provide significant benefits for patients.
Find out about our other research in this area:
