The depletion of reactive astrocytes causes the glioblastoma to regress

The depletion of reactive astrocytes causes the glioblastoma to regress

A groundbreaking study at Tel Aviv University has effectively eradicated glioblastoma, a highly deadly type of brain tumor. The researchers achieved the result using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other provides the energy needed for rapid tumor growth. The work found that both mechanisms are controlled by brain cells called astrocytes and in their absence the tumor cells die and are eliminated.

The study was conducted by Ph.D. Student Rita Perelroizen, under the direction of Dr. Lior Mayo from the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin from the National Institutes of Health (NIH) in the USA. The paper was published in the scientific journal Brain and highlighted with a special commentary.

The researchers explain: "Glioblastoma is an extremely aggressive and invasive brain tumor for which there is no known effective treatment. The tumor cells are highly resistant to all known therapies, and unfortunately the life expectancy of patients has not increased significantly in the last 50 years. Our results provide a promising basis for the development of effective drugs to treat glioblastoma and other types of." Brain tumors.”

Here we have approached the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supporting microenvironment, the tissue that surrounds the tumor cells. In particular, 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. Over the past decade, research by us and others has revealed additional astrocyte functions that either alleviate or worsen 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 glioblastoma tumor growth.”

Dr. Lior Mayo, Shmunis School of Biomedicine and Cancer Research, Tel Aviv University

Using an animal model in which they could 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. Using a unique method to specifically eliminate the astrocytes near the tumor, they observed a dramatic result: the cancer disappeared within a few days and all treated animals survived. In addition, most animals survived even after treatment was discontinued.

Dr. Mayo: "In the absence of astrocytes, the tumor disappeared quickly, and in most cases there was no relapse - suggesting that the astrocytes are essential for tumor progression and survival. Therefore, we examined the underlying mechanisms: How do astrocytes change from cells that support normal brain activity to cells that support growth." of malignant tumors?” To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.

They found two main differences - identifying the changes astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma. Dr. Mayo: "The tumor mass contains up to 40% immune cells - mostly macrophages that are recruited from the blood or the brain itself. In addition, astrocytes can send signals that call immune cells to locations in the brain that need protection." In this study, we found that astrocytes continue to fulfill this role even in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes “persuade” them to “switch sides” and support the tumor instead of attacking it. We found that the astrocytes alter the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and promoting its growth.”

The second change by which astrocytes support glioblastoma is by modulating their access to energy – via the production and transfer of cholesterol to tumor cells. Dr. Mayo: "The malignant glioblastoma cells divide rapidly, a process that requires a lot of energy. Since they block access to energy sources in the blood through the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself - namely in the "cholesterol factory" of astrocytes, which normally supplies neurons and other brain cells with energy. We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and deliver it to the cancer cells. Therefore, we hypothesized that since the tumor relies on this cholesterol as its main source of energy, depriving it of this intake will starve the tumor.”

Next, the researchers manipulated the astrocytes near the tumor to stop the expression of a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: Without access to the cholesterol produced by astrocytes, the tumor essentially “starved” in just a few days. These remarkable results were obtained in both animal models and glioblastoma samples from human patients and are consistent with the researchers' starvation hypothesis.

Dr. Mayo notes: "This work sheds new light on the role of the blood-brain barrier in the treatment of brain diseases. 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 difficult to deliver drugs to the brain and represents a barrier to treatment. Our results suggest so suggests that the blood-brain barrier, at least in the specific case of glioblastoma, may be beneficial in future treatments because it creates a unique vulnerability - the tumor's dependence on cholesterol produced in the brain. We believe this weakness may lead to a unique therapeutic opportunity.”

The project also examined databases of hundreds of human glioblastoma patients and correlated them with the results described above. The researchers explain: "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 and thus supported." the concept that the identified genes and processes are important for the survival of glioblastoma patients.”

Dr. Mayo concludes: "Currently, tools to eliminate the astrocytes surrounding 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 can be repurposed to address the mechanisms identified in this study." "We believe the conceptual breakthroughs of this study will accelerate success in the fight against glioblastoma. We hope our findings will serve as a foundation for the development of effective treatments for this deadly disease, brain cancer and other types of brain tumors."

Source:

Tel Aviv University

Reference:

Perelroizen, R., et al. (2022) Astrocyte immunometabolic regulation of the tumor microenvironment drives glioblastoma pathogenicity. Brain. doi.org/10.1093/brain/awac222.

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