Groundbreaking new study effectively treats brain cancer

The work serves as a foundational guide for clinicians and scientists to understand disease progression and improve treatment outcomes. (CREDIT: Creative Commons)

Dramatic findings in glioblastoma research: Removal of astrocytes (a major class of brain cells) surrounding tumors, or suppression of their ability to supply energy to glioblastoma cells, resulted in cancer cell death and tumor regression within days.

Researchers: “These results provide a promising basis for the development of effective drugs for glioblastoma, aggressive and so far untreatable cancer, and other types of brain tumors.”

A groundbreaking study at Tel Aviv University has effectively eradicated glioblastoma, a very deadly type of brain cancer. The researchers achieved the result using a method they developed based on the discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, and the other supplies the energy needed for rapid tumor growth.

In the course of the work, it was found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, tumor cells die and are destroyed.

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The study was led by Ph.D. student Rita Perelroizen under the supervision of Dr. Lior Mayo from the School of Biomedicine and Cancer Research. Schmunis and the Sagol School of Neurology in collaboration with Prof. Eitan Ruppin of the National Institutes of Health (NIH) in the USA. Article published in a scientific journal Brain and was highlighted with a special comment.

The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain cancer for which there is no known effective treatment. Tumor cells are highly resistant to all known treatments, and, unfortunately, the life expectancy of patients has not increased significantly over the past 50 years. years old. Our results provide a promising basis for the development of effective drugs for the treatment of glioblastoma and other types of brain tumors.”

Dr. Mayo: “Here we approach the problem of glioblastoma from a new perspective. Instead of focusing on the tumor, we focused on its supportive microenvironment, i.e. the tissue that surrounds the tumor cells. In particular, we studied astrocytes, the main 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, our and other studies have identified additional functions of astrocytes that either alleviate or exacerbate various brain diseases. Under the microscope, we found that activated astrocytes surround glioblastoma tumors. Based on this observation, we decided to investigate the role of astrocytes in glioblastoma tumor growth.”

Using an animal model in which they could eliminate active astrocytes around a tumor, the researchers found that in the presence of astrocytes, cancer killed all animals with glioblastoma tumors within 4-5 weeks.

Using a unique method of specifically killing astrocytes in the vicinity of the tumor, they achieved a dramatic result: the cancer disappeared within a few days, and all treated animals survived. Moreover, even after treatment was stopped, most of the animals survived.

Dr. Mayo: “In the absence of astrocytes, the tumor quickly disappeared and in most cases there was no recurrence, indicating that astrocytes are essential for tumor progression and survival. So we explored the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity to cells that support the growth of malignant tumors?” To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and those from glioblastoma tumors.

They found two main differences – thereby revealing the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.

Dr. Mayo: “The tumor mass includes up to 40% of immune cells – mostly macrophages recruited from the blood or from the brain itself. In addition, astrocytes can send signals that trigger immune cells in areas of the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the triggered immune cells reach the tumor, the astrocytes “coax” them to “come to the other side” and support the tumor rather than attack it. In particular , we found that 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 the regulation of their access to energy through the production and transport of cholesterol to tumor cells.

Dr. Mayo: “Glioblastoma malignant cells divide rapidly, and this process requires a lot of energy. Having access to energy sources in the blood, closed by 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 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 since the tumor depends on this cholesterol as its main source of energy, the elimination of this store would lead to depletion of the tumor.”

The researchers then engineered astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing cholesterol from being released into the tumor.

Once again, the results were impressive: without access to the cholesterol produced by astrocytes, the tumor actually “starved to death” in just a few days. These remarkable results were obtained both in animal models and in glioblastoma samples taken from patients, and are consistent with the researchers’ hypothesis of starvation.

Dr. Mayo notes: “This work sheds new light on the role of the blood-brain barrier in the treatment of brain disease. The usual purpose of this barrier is to protect the brain by preventing substances from passing from the blood into the brain. But in the case of brain disease, this barrier makes it difficult to deliver drugs to the brain and is considered an impediment to treatment. Our results suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be useful for future treatments because it creates a unique vulnerability − dependence of the tumor on cholesterol produced by the brain. We think this weakness could turn into a unique therapeutic opportunity.”

The project also examined databases of hundreds of human glioblastoma patients and compared them with the results described above.

The researchers explain: “For each patient, we studied the expression levels of genes that either neutralize the immune response or provide the tumor with cholesterol-based energy.”

He further explained: “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 patients with glioblastoma.”

Dr. Mayo concludes: “Currently, tools to eliminate astrocytes surrounding a tumor are available in animal models, but not in humans. The challenge now is to develop drugs that target specific processes in astrocytes that promote tumor growth. drugs can be redirected to inhibit the mechanisms identified in this study. We believe that the conceptual breakthroughs obtained in this study will accelerate success in the fight against glioblastoma. We hope that our results will serve as a basis for the development of effective treatments for this deadly brain cancer. brain and other types of brain tumors.

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Note: Materials provided above by Tel Aviv University. Content can be edited for style and length.

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