New ‘starvation’ method eliminates aggressive brain tumors in mice

Tel Aviv University researchers conducted a landmark study in which they found a way to eliminate deadly brain cancer 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 stellateA type of cell that supports a neuron. There are no effective treatments currently available, and the life expectancy of glioblastoma patients has not improved significantly in the past 50 years.

Astrocytes support glioblastoma growth

Researchers have developed a method that targets two important brain mechanisms associated with supporting glioblastoma growth and survival. One mechanism protects cancer cells from being attacked by immune systemThe other “feeds” tumors to help them grow. The study found that both systems are controlled by astrocytes that surround tumors, and that in the absence of astrocytes, cancer cells become unable to support themselves and eventually die.

Dr.. Lior MayD., assistant professor at Tel Aviv University and senior author of the study, explained: “Here, we approached the glioblastoma challenge from a new angle. Instead of focusing on the tumor, we focused on the microenvironment supporting it, that is, the tissue surrounding the tumor cells. Specifically, we studied the cells Astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named because of their star-like shape.Over the past decade, research by us and others has revealed additional astrocyte functions that either alleviate or exacerbate brain diseases. Under the microscope, we found that activated astrocytes surround glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma growth.”

The team used a mouse model of glioblastoma in which they could selectively eliminate astrocytes located around the tumors. When these astrocytes were present, the cancer led to the death of all the animals within four to five weeks. When the astrocytes close to the tumors were removed, the tumor cells were eliminated within a few days and all the animals survived. Given these startling findings, Mayo stressed the need to investigate the processes driving these effects: “In the absence of astrocytes, the tumor disappeared rapidly and, in most cases, there was no relapse—suggesting that astrocytes are essential for tumor development and survival.” Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity to cells that support the growth of malignancy?”

To explore this further, the researchers analyzed astrocytes taken from healthy brains and from glioblastomas to investigate any changes in gene expression. This showed that astrocytes from glioblastoma have two main differences compared to astrocytes from normal tissues.

First, in the immune response. Under normal circumstances, astrocytes help activate and attract immune cells in the brain. This is still the case in glioblastomas – however, they can also make immune cells “switch sides”, helping to preserve cancer cells rather than attacking them.

Second, stellate cells in glioblastoma can also affect the access of cancer cells to energy sources, particularly cholesterol. Astrocytes produce cholesterol, which supplies energy to nerve cells and other brain cells. Glioblastoma cells divide rapidly and require large amounts of energy – however, The blood-brain barrier It can block access to many energy sources. Therefore, stellate cells in glioblastoma increase cholesterol production to “feed” the cancer cells. As a result, the researchers hypothesized that eliminating the source of cholesterol would “starve” glioblastoma cells.

Targeting Cholesterol Dependence

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

Mayo explained, “This work sheds new light on the role of the blood-brain barrier in the treatment of brain diseases. The natural purpose of this barrier is to protect the brain by preventing the passage of substances from the blood into the brain. But in the case of a disease in the brain, this barrier makes it difficult Delivery of drugs to the brain is considered an obstacle to treatment.Our findings, at least in the case of glioblastoma, suggest that the blood-brain barrier may be useful for future therapies, as it generates a unique weakness – the tumor’s dependence on cholesterol from the brain. This weakness can translate into a unique treatment opportunity.”

In addition, the researchers studied gene expression databases from several hundred glioblastoma patients to see if they could find the same effect. They scanned expression information for genes involved in neutralizing the immune response or providing cells with cholesterol. 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 eradicate peritumoral astrocytes are available in animal models, but not in humans,” Mayo summarizes. The challenge now is to develop drugs that target the specific processes in astrocytes that promote tumor growth. Alternately, existing drugs can be redirected to inhibit the mechanisms identified in this study. We believe that the conceptual breakthroughs provided by this study 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 fatal brain cancer and other types of brain tumors.”

Reference: Perelroizen R, Philosof B, Budick-Harmelin N, and others. Immunoregulatory regulation of astrocytes in the tumor microenvironment induces pathogenesis in glioblastoma. brain. 2022: aawac222. dui: 10.1093/Brain/awac222

This article is a paraphrase of a press release issued by Tel Aviv University. Articles have been edited for length and content.