Brain support cells called astrocytes have long been found around glioblastomas, leading scientists to believe that cells come together to help fight tumors, but recent studies have shown that cells instead help growth cancer. An article published on July 28 in Brain provides further evidence that astrocytes contribute to glioblastoma progression and identifies the mechanism by which they do so.
“We misinterpreted astrocytes and thought they were protecting the brain, but it really helped the tumor,” says Frank Winkler, a neuro-oncologist at Heidelberg University Hospital, who was not part of the study. “It always looked like the brain was defending itself and fighting off the tumor, but now we know the astrocytes don’t actually help.”
Astrocytes regulate the flow of substances through the blood-brain barriermaintain the neural microenvironment, and since cholesterol produced elsewhere in the body cannot cross the blood-brain barrier, astrocytes produce enough cholesterol to support the brain. The cells have been implicated in the pathogenesis of other types of brain tumors and have been shown create a welcoming environment for glioblastoma. In the new study, researchers from Tel Aviv University demonstrate that astrocytes do indeed support the pathogenesis of glioblastoma after the initial onset of the disease, both by remodeling immune cells to support tumor growth and by fueling the tumor with enough cholesterol to keep it alive.
The researchers first implanted mouse glioblastoma cells into six wild-type mice and six others that lacked astrocytes. They noticed that mice without astrocytes developed significantly smaller tumors and lived longer than wild-type animals, indicating that astrocytes play a role in the progression of glioblastoma.
The researchers then looked at how astrocytes influence cancer metabolism. They conducted a genetic analysis on astrocytes of mice with and without glioblastoma tumors and noticed an increase in the expression levels of genes that disrupted metabolic processes in the former. When they analyzed the distribution of cholesterol in the brains of mice bearing glioblastoma cells, the researchers found a higher amount of cholesterol in the tumor than in the surrounding environment.
Now we know astrocytes don’t really help.
—Frank Winkler, University Hospital, Heidelberg
To understand the effect of cholesterol synthesized by astrocytes on the pathogenesis of glioblastoma, the researchers cultured glioblastoma cells alongside astrocytes. When they starved the cancer cells of cholesterol, they discovered that the astrocytes produced more of an enzyme that controls cholesterol synthesis. A similar event had also been observed in a study by a different group, which examined sequenced cell lines derived from the tumors of four glioblastoma patients. This indicates that the researchers behind the Brain A study indicates that glioblastomas threatened with death by cholesterol deprivation recruit astrocytes to save them.
To study the mechanism by which this occurs, the researchers knocked out the gene in the astrocyte that codes for ABCA1, a protein that facilitates the movement of cholesterol in the brain, then cultured the glioblastoma cells alongside the astrocytes in a cholesterol-free medium. They discovered that astrocytes could not save cancer cells, which died due to reduced cholesterol availability.
In another experiment in mice, researchers blocked the flow of cholesterol into glioblastoma tumors and found that this caused tumor size to decrease and also prolonged the survival of tumor-bearing mice. “We show that if we down-regulate the proteins responsible for the major efflux of cholesterol from astrocytes to glioblastoma cells, then we can significantly reduce tumor size and significantly improve mouse survival,” says the co-author of the study. Lior Mayo, a neurobiologist at Tel Aviv University. He says this result is “very interesting” because it aligns with data gleaned from the Cancer Genome Atlas showing that glioblastoma patients with low levels of ABCA1 tend to survive longer than those with higher levels of protein.
Currently, glioblastoma is treated by killing cancer cells with chemotherapy and radiotherapy, and with immunotherapies that stimulate the body’s own defenses. Mayo suggests that combining these strategies with depriving the tumor of cholesterol would attack it in several directions: “Targeting the metabolism and energy production needed by the tumor is a kind of paradigm shift that will have a synergistic effect ” in the treatment of this type. cancer, he said.