New method “starves” and eliminates aggressive brain tumors in mice

Researchers from Tel Aviv University have conducted a groundbreaking study in which they have found a way to eradicate the deadly brain cancer glioblastoma in mice. The study was published in the journal Brain.

What is glioblastoma??

Glioblastoma is an aggressive and invasive cancer that develops in the brain or spinal cord. These cancers develop from astrocytes, a type of cell that supports nerve cells. There are currently no effective treatments available and the life expectancy of glioblastoma patients has not improved significantly over the past 50 years.

Astrocytes support the growth of glioblastoma

The researchers developed a method that targets two key mechanisms in the brain associated with supporting glioblastoma growth and survival. One mechanism protects cancer cells from immune system attacks, and the other “feeds” the tumors to help them grow. The study found that both systems are controlled by the astrocytes surrounding the tumors, and that when astrocytes are absent, tumor cells are unable to support themselves and eventually die.

dr. Lior Mayo, assistant professor at Tel Aviv University and senior author of the study, explains: “Here we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on the supportive microenvironment, that is, the tissue surrounding the tumor cells.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. “Over the past decade, research by us and others has revealed additional functions of astrocytes that alleviate or exacerbate various brain diseases. Under the microscope, we discovered 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.”

The team used a mouse model of glioblastoma in which they could selectively eliminate astrocytes around the tumors. When these astrocytes were present, cancer resulted in the death of all animals within four to five weeks. When the astrocytes near the tumors were removed, the cancer cells were eliminated within days and all the animals survived. Given these striking findings, Mayo emphasized the need to investigate the processes that cause these effects: “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. have we explored the underlying mechanisms: how do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?”

To explore this further, the researchers analyzed astrocytes from healthy brains and from glioblastoma to examine any changes in gene expression. This showed that astrocytes from glioblastomas had two major differences from astrocytes from normal tissue.

First, in the immune response. Under normal circumstances, astrocytes help to activate and recruit immune cells in the brain. This remains the case with glioblastoma, but they can also cause immune cells to switch sides, helping to support cancer cells rather than attacking them.

Second, astrocytes in glioblastoma may also affect tumor cells’ access to energy sources, primarily cholesterol. Astrocytes produce cholesterol that provides energy to neurons and other brain cells. Glioblastoma cells divide quickly and require large amounts of energy, but the blood-brain barrier can block access to many energy sources. Therefore, astrocytes in glioblastoma increase their cholesterol production to “feed” tumor cells. As a result, the researchers hypothesized that eliminating the source of cholesterol would “starve” and eliminate glioblastoma cells.

Targeting cholesterol dependence

To starve glioblastoma cells of their energy source, astrocytes near the tumors were engineered to block the expression of a protein called ATP-binding cassette transporter A1 (ABCA1). This is a transport protein that exports cholesterol from cells. Therefore, blocking ABCA1 prevents astrocytes from releasing cholesterol. With their source of cholesterol gone, glioblastoma cells “starved” within a few days. These experiments were performed in mice as well as in glioblastoma samples taken from human patients.

“This work sheds new light on the role of the blood-brain barrier in treating brain diseases,” Mayo explains. “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 dependence on brain-produced cholesterol. We think this weakness could translate into a unique therapeutic opportunity.”

In addition, the researchers examined databases of gene expression data from several hundred glioblastoma patients to see if they could find the same effect. They scanned the expression information looking for genes involved in neutralizing the immune response or delivering cholesterol to cells. The results indicated that patients with low expression of these genes lived longer, supporting the hypothesis that these processes are vital for glioblastoma development.

“Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans,” Mayo summarizes. “The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternatively, existing drugs can be reused to inhibit mechanisms identified in this study. We believe the conceptual breakthroughs that this study provides will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for developing effective treatments for these deadly brain cancers and other types of brain tumors.”

Reference: Perelroizen R, Philosopher B, Budick-Harmelin N, et al. Astrocyte immunometabolic regulation of the tumor microenvironment stimulates the pathogenicity of glioblastoma. Brain. 2022:awac222. doi: 10.1093/brain/awac222

This article is adapted from a Tel Aviv University press release. Material has been edited for length and content.

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