Deadly brain tumours can be starved of their energy source

Researchers from Tel Aviv University have announced they have effectively eradicated glioblastoma — a highly lethal type of brain cancer — using a method they developed based on their discovery of two critical mechanisms in the brain that support tumour growth and survival. Published in the journal Brain, the work found that both mechanisms are controlled by brain cells called astrocytes — in their absence, the tumour cells die and are eliminated.

Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumour cells are highly resistant to all known therapies, and patient life expectancy has not increased significantly in the last 50 years. Looking to tackle the challenge of glioblastoma from a new angle, the researchers chose to focus on the tissue that surrounds the tumour cells, rather than the tumour itself.

“Specifically, we studied astrocytes — a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their star-like shape,” said Dr Lior Mayo, who supervised study leader and PhD student Rita Perelroizen.

“Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope, we found that activated astrocytes surrounded glioblastoma tumours. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumour growth.”

Using an animal model, in which they could eliminate active astrocytes around the tumour, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumours within 4–5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumour, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived.

“In the absence of astrocytes, the tumour quickly disappeared, and in most cases there was no relapse — indicating that the astrocytes are essential to tumour progression and survival,” Mayo said. “Therefore, we investigated the underlying mechanisms: how do astrocytes transform from cells that support normal brain activity into cells that support malignant tumour growth?”

To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumours. They found two main differences, thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.

“The tumour mass includes up to 40% immune cells — mostly macrophages recruited from the blood or from the brain itself,” Mayo said. “Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfil this role in the presence of glioblastoma tumours. However, once the summoned immune cells reach the tumour, the astrocytes persuade them to ‘change sides’ and support the tumour instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumour both directly and indirectly — thereby protecting the tumour and facilitating its growth.”

The second change through which astrocytes support glioblastoma is by modulating their access to energy — via the production and transfer of cholesterol to the tumour cells. Mayo said, “The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood–brain barrier, they must obtain this energy from the cholesterol produced in the brain itself — namely in the astrocytes’ ‘cholesterol factory’, which usually supplies energy to neurons and other brain cells.

“We discovered that the astrocytes surrounding the tumour increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesised that, because the tumour depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumour.”

Next, the researchers engineered the astrocytes near the tumour to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumour. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumour essentially ‘starved’ to death in just a few days. These results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis.

“This work sheds new light on the role of the blood–brain barrier in treating brain diseases,” Mayo said. “The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood–brain barrier may be beneficial to future treatments, as it generates a unique vulnerability — the tumour’s dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”

The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described. The researchers explained, “For each patient, we examined the expression levels of genes that either neutralise the immune response or provide the tumour with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients.”

Mayo concluded, “Currently, tools to eliminate the astrocytes surrounding the tumour are available in animal models, but not in humans. The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumour growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumours.”

Image credit: iStock.com/peterschreiber.media

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