New Method "Starves" and Eliminates Aggressive Brain Tumors in Mice
Tel Aviv University researchers have carried out a landmark study in which they have found a way to eradicate the lethal 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. No effective treatments are currently available, and the life expectancy of glioblastoma patients has not significantly improved in the last 50 years.
Astrocytes support glioblastoma growth
The researchers developed a method that targets two important mechanisms in the brain that are associated with supporting the growth and survival of glioblastoma. One mechanism shields cancer cells from being attacked by the immune system, and the other “feeds” the tumors to help them grow. The study found that both systems are controlled by the astrocytes that surround 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, explained, “Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells. Specifically, we studied astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate 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.”
The team used a mouse model of glioblastoma in which they could selectively eliminate astrocytes found around the tumors. When these astrocytes were present, cancer led to the death of all animals within four to five weeks. When the astrocytes near the tumors were removed, the cancer cells were eliminated within a few days and all animals survived. Considering these striking findings, Mayo emphasized the need to investigate the processes driving 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 to tumor progression and survival. Therefore, we investigated 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 taken from healthy brains and from glioblastoma to investigate any changes in gene expression. This showed that astrocytes taken from glioblastomas had two major differences compared to astrocytes from normal tissue.
Firstly, in the immune response. In normal conditions, astrocytes help to activate and attract immune cells in the brain. This remains the case in glioblastoma – however, they also can make immune cells “switch sides”, where they help to sustain cancer cells instead of attacking them.
Secondly, astrocytes in glioblastoma can also influence tumor cells’ access to energy sources, mainly cholesterol. Astrocytes produce cholesterol that supplies energy to neurons and other brain cells. Glioblastoma cells divide rapidly and require large amounts of energy – however, the blood–brain barrier can block access to many sources of energy. 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 dependence on cholesterol
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 transporter protein that exports cholesterol from cells. Therefore, blocking ABCA1 prevents astrocytes from releasing cholesterol. With their source of cholesterol gone, glioblastoma cells “starved” to death within a few days. These experiments were performed in both mice and 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 explained. “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 event of a brain disease, this barrier makes it challenging to deliver medications 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 to future treatments, as it generates a unique vulnerability – the tumor's dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”
Additionally, the researchers investigated databases of gene expression data taken 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 supplying cells with cholesterol. The results indicated that patients who had 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. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think 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 this deadly brain cancer and other types of brain tumors.”
Reference: Perelroizen R, Philosof B, Budick-Harmelin N, et al. Astrocyte immunometabolic regulation of the tumor microenvironment drives glioblastoma pathogenicity. Brain. 2022:awac222. doi: 10.1093/brain/awac222