A team of Israeli researchers based at Tel Aviv University have recently published research showing that eliminating or inhibiting the ability of brain cells called astrocytes to provide energy to glioblastoma cells resulted in cancer cell death and tumor regression. The team developed a method to achieve these results after discovering two mechanisms in the brain that support tumor growth and survival. One protects cancer cells from the immune system, and the other supplies the energy required for rapid tumor growth. Both mechanisms are controlled by astrocytes and, in their absence, the tumor cells die and are eliminated.
“Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment,” the researchers noted in their paper published in the journal Brain. “The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.”
The study was led by doctoral candidate Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH).
For their study, the researchers used an animal model that allowed them to eliminate active astrocyte around the tumor. Applying their method to eradicate the astrocytes, the investigators found that all the cancer disappeared in the animals within days and all the animals survived. Animals that had the presence of astrocytes near their tumor all died within five weeks.
“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,” Mayo said. “Specifically, we studied astrocytes—a major class of brain cells that support normal brain function. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases.
“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,” Mayo continued. But why did the astrocytes behave this way, essentially changing from cells that support normal brain activity to ones that help foster tumor growth. To get to the bottom of this, the researchers compared the gene expression profiles of astrocytes from health brains with those from glioblastoma tumors.
The team found two significant differences. The first related to how the immune system responded to glioblastoma. “The tumor mass includes up to 40% immune cells – mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in 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 summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it,” Mayo said.
The second change noted was how the astrocytes helped modulate glioblastoma’s access to energy needed to thrive, via the production and transfer of cholesterol to tumor cells. The investigators hypothesized that since the tumor cells were reliant on the cholesterol produced by the astrocytes as their main source of energy, eliminating it would starve the tumor.
To test their theory, Mayo and team engineered astrocytes near the tumor to stop expressing the specific protein—ABCA1—that transports cholesterol, effective preventing it from supplying the tumor. This method also produced good results, with the glioblastoma tumor dying within days. The researchers achieved these results in both animal models and glioblastoma samples taken from human patients.
“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 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,” Mayo concluded.