December 8, 2022

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Breakthrough method ‘starves’ highly lethal cancer tumors and eradicates them

Breakthrough method ‘starves’ highly lethal cancer tumors and eradicates them



 

Breakthrough method ‘starves’ highly lethal cancer tumors and eradicates them

Breakthrough research at Tel Aviv University has successfully eradicated glioblastoma, a deadly form of brain cancer.

The researchers achieved this result by developing a strategy based on two key mechanisms they discovered in the brain that promote tumor growth and survival: One mechanism provides cancer cells with protection from the immune system, while the other provides protection from the immune system. Rapid tumor growth provides the necessary energy.

 

The study found that astrocytes, which are brain cells, regulate both approaches, and when they are absent, tumor cells die and are cleaned up.

 

PhD student Rita Perelroizen served as the study’s principal investigator.

She collaborated with Professor Eytan Ruppin of the National Institutes of Health (NIH) and was supervised by Dr. Lior Mayo of the Shmunis School of Biomedical and Cancer Research and the Sagol School of Neuroscience in Tel Aviv. The study was recently published in the journal Brain with peer review.

 

the researchers explained. “Glioblastoma is an extremely aggressive and invasive type of brain cancer for which there is currently no known effective treatment. The tumor cells are highly resistant to all known treatments, sadly , the life expectancy of patients has not increased significantly over the past 50 years. Our findings provide a promising basis for developing effective drugs to treat glioblastoma and other types of brain tumors.”

 

Breakthrough method 'starves' highly lethal cancer tumors and eradicates them

Dr. Lior Mayo Source: Tel Aviv University

 

Dr. Mayo: “Here, we approach the challenge of glioblastoma from a new perspective. Instead of focusing on the tumor, we focus on its supportive microenvironment, the organization that surrounds tumor cells. Specifically, we study Astrocytes – a major class of brain cells that support normal brain function, were discovered about 200 years ago and named for their star shape. Over the past decade, research by ours and others has revealed that stars Other functions of astrocytes that can alleviate or exacerbate various brain diseases. Under the microscope, we found that activated astrocytes surround glioblastoma tumors. Based on this observation, we set out to study astrocytes The role of myeloblasts in glioblastoma tumor growth”.

 

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

Applying a unique method that specifically eradicated astrocytes near the tumor, the researchers observed a dramatic result: The cancer disappeared within a few days, and all treated animals survived. Furthermore, most animals survived even after stopping treatment.

 

Dr. Mayo: “In the absence of astrocytes, the tumor disappeared rapidly and in most cases did not recur — suggesting that astrocytes are critical for tumor progression and survival. We therefore investigated the underlying mechanisms. How do glial cells switch from cells that support normal brain activity to cells that support the growth of malignant tumors?” To answer these questions, the researchers compared gene expression in astrocytes isolated from healthy brain and glioblastoma tumors .

 

Breakthrough method 'starves' highly lethal cancer tumors and eradicates them

Dr. Lior-Mayo with students. Source: Tel Aviv University

 

They found two major differences — thereby identifying the changes astrocytes undergo when exposed to glioblastoma. The first change is the immune response to glioblastoma.

 

Dr. Mayo: “The tumor mass includes up to 40 percent of immune cells – mostly macrophages recruited from the blood or the brain itself. In addition, astrocytes can signal that summoning immune cells to the brain need protection place. In this study, we found that astrocytes continue to perform this role in the presence of glioblastoma. However, once the summoned immune cells reach the tumor, astrocytes ” Persuading “they” to “change their stance” in favor of the tumor rather than attacking it. Specifically, we found that astrocytes altered the ability of recruited immune cells to attack the tumor directly and indirectly — thereby protecting the tumor and promoting it growth.”

 

A second change in astrocytes supporting glioblastoma is by modulating them for energy — by producing and transferring cholesterol into tumor cells.

 

Dr. Mayo: “Malignant glioblastoma cells divide rapidly, and this process requires a lot of energy. Since the blood-brain barrier blocks access to a source of energy in the blood, they must obtain this energy from cholesterol produced by the brain itself — The ‘cholesterol factories’ of astrocytes, which normally supply energy to neurons and other brain cells. We found that astrocytes around tumors increase cholesterol production and supply it to cancer cells. Therefore, we hypothesized that since tumors depend on this cholesterol as their primary energy source, eliminating this supply will starve the tumor.”

 

Next, the researchers engineered astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), preventing them from releasing cholesterol into the tumor.

Once again, the results were dramatic: The tumors essentially “starved” to death in just a few days due to the lack of access to the cholesterol produced by the astrocytes.

These remarkable results were obtained in animal models and glioblastoma samples from human patients, consistent with the researchers’ starvation hypothesis.

 

Dr. Mayo noted. “This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing substances from entering the brain from the blood. But when brain disease occurs, this The barrier makes drug delivery to the brain challenging and is considered a barrier 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 produces A unique vulnerability — the tumor’s dependence on cholesterol produced by the brain. We think this vulnerability can translate into a unique therapeutic opportunity.”

 

The project also examined a database of hundreds of human glioblastoma patients and correlated them with the above-mentioned results.

 

the researchers explained. “For each patient, we examined the expression levels of genes that neutralize the immune response or provide the tumor with cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, supporting such a concept that identified genes and processes are important for the survival of glioblastoma patients”.

 

Dr. Mayo concluded. “Currently, tools to eliminate peritumoral astrocytes 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. There are drugs that can be repurposed to inhibit the mechanisms identified in this study. We believe that the conceptual breakthrough provided by this study will accelerate success in combating glioblastoma. We hope our findings will serve as a catalyst for the development of effective treatments for this The basis of deadly brain cancer and other types of brain tumors”.

 

 

 

Breakthrough method ‘starves’ highly lethal cancer tumors and eradicates them

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