Glioblastoma is an extremely aggressive and invasive brain cancer for which there is no known effective treatment. The tumor cells are highly resistant to all known therapies and the patient’s life expectancy has not increased significantly over the past 50 years. To tackle the challenge of glioblastoma from a new angle, the researchers chose to focus on the tissue surrounding the tumor cells, rather than the tumor itself.
“In particular, we studied astrocytes — an important 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, our and others’ research has uncovered additional functions of astrocytes that alleviate or exacerbate various brain diseases. Under the microscope, we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in the growth of glioblastoma tumors.”
Using an animal model, in which they were able to eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks. By applying a unique method to specifically eradicate the astrocytes near the tumor, they saw a dramatic result: the cancer disappeared within days and all treated animals survived. In addition, most animals survived even after treatment discontinuation.
“In the absence of astrocytes, the tumor quickly disappeared and in most cases there was no relapse — indicating that the astrocytes are essential for tumor progression and survival,” Mayo said. “So we explored the underlying mechanisms: how do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?”
To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors. They found two key differences, identifying the changes astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.
“The tumor mass includes up to 40% immune cells — usually macrophages recruited from the blood or from the brain itself,” Mayo said. “In addition, astrocytes can send signals that call immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. But once the summoned immune cells reach the tumor, the astrocytes convince them to “switch sides” and support the tumor instead of attacking it. In particular, we found that the astrocytes alter the ability of recruited immune cells to attack the tumor both directly and indirectly – protecting the tumor and facilitating its growth.”
The second change by which astrocytes support glioblastoma is by modulating their access to energy – through the production and transfer of cholesterol to the tumor cells. Mayo said: “The malignant glioblastoma cells divide quickly, a process that requires a lot of energy. With access to energy sources in the blood that are blocked by the blood-brain barrier, they have to get this energy from the cholesterol produced in the brain itself — namely in the “cholesterol factory” of the astrocytes, which usually supplies energy to neurons and other brain cells .
“We found that the astrocytes surrounding the tumor increase the production of cholesterol and deliver it to the cancer cells. Therefore, we hypothesized that because the tumor relies on this cholesterol as its main source of energy, eliminating this supply will starve the tumor.”
Next, the researchers manipulated the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), preventing them from releasing cholesterol into the tumor. Again, the results were dramatic: Without access to the cholesterol produced by astrocytes, the tumor ‘starved’ 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’ hunger 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 case of brain disease, this barrier makes it challenging to deliver drugs 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 for future treatments because it generates a unique vulnerability – the tumor’s reliance on brain-produced cholesterol. We think this weakness could translate into a unique therapeutic opportunity.”
The project also examined databases of 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 neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, supporting the concept.” that the identified genes and processes are important for the survival of glioblastoma patients.”
Mayo concluded: “Currently, tools to eliminate the astrocytes around the tumor 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 tumor growth. Alternatively, existing drugs are being reused to inhibit mechanisms identified in this study. We believe the conceptual breakthroughs this study provides 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 these deadly brain cancers and other types of brain tumors.”
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