ABOVE: A glioblastoma tumor (white) surrounded by astrocytes (teal) Lior Mayo
Brain support cells called astrocytes have long been found around glioblastomas, leading scientists to think that the cells rally to help fight the tumors, but recent studies have found that the cells instead aid the growth of the cancer. A paper 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 have misinterpreted astrocytes and thought it is protecting the brain, but it was really helping the tumor,” says Frank Winkler, a neuro-oncologist at the University Hospital, Heidelberg, who was not part of the study. “It always seemed like the brain is defending itself and it’s fighting the tumor, but now we know the astrocytes aren’t actually helping.”
Astrocytes regulate the flow of substances through the blood-brain barrier, maintain the neural microenvironment, and, because cholesterol produced elsewhere in the body can’t 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 found to create a welcoming environment for glioblastoma. In the new study, researchers at Tel Aviv University demonstrate that astrocytes do indeed support glioblastoma pathogenesis after the initial onset of the disease, both by remodeling immune cells to support tumor growth and by feeding the tumor with enough cholesterol to keep it alive.
The researchers first implanted mouse glioblastoma cells in six wildtype mice and another six that lacked astrocytes. They noticed that the mice without astrocytes developed considerably smaller tumors and lived longer than the wildtype animals, indicating that astrocytes play a role in glioblastoma progression.
The researchers next looked at how astrocytes influenced the cancer’s metabolism. They conducted a genetic analysis on astrocytes of mice with glioblastoma tumors and those without, and noticed an increase in the expression levels of genes that disrupted metabolic processes in the former. When they analyzed the distribution of cholesterol across the brains of mice bearing glioblastoma cells, the researchers found a higher quantity of cholesterol in the tumor than in the surrounding environment.
Now we know the astrocytes aren’t actually helping.
—Frank Winkler, University Hospital, Heidelberg
To understand the effect of cholesterol synthesized by astrocytes on glioblastoma pathogenesis, the researchers cultured glioblastoma cells alongside astrocytes. When they deprived the cancer cells of cholesterol, they found that the astrocytes produced more of an enzyme that controls cholesterol synthesis. A similar occurrence had also been observed in a different group’s study, which looked at sequenced cell lines derived from the tumors of four glioblastoma patients. This indicates, the researchers behind the Brain study say, that glioblastomas facing death by cholesterol deprivation recruit astrocytes to rescue them.
To study the mechanism through which this happens, the researchers knocked out the astrocyte gene that codes for ABCA1, a protein that aids the movement of cholesterol in the brain, then cultured the glioblastoma cells alongside astrocytes in a cholesterol-free medium. They found that the astrocytes could not rescue the cancer cells, which died due to reduced cholesterol availability.
In another experiment in mice, the researchers blocked the flow of cholesterol into the glioblastoma tumors, and found that this caused the tumor to shrink in size and also extended the survival of the tumor-bearing mice. “We show that if we downregulate the proteins responsible for the main efflux of cholesterol from astrocytes to the glioblastoma cells, then we can dramatically reduce the size of the tumors and significantly enhance the survival of the mice,” says study coauthor 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 the protein.
Currently, glioblastoma is treated by killing cancerous cells with chemotherapy and radiation, and with immunotherapies that rev up the body’s own defenses. Mayo suggests that combining these strategies with starving the tumor of cholesterol would attack it from multiple directions: “Targeting the metabolism and the energy production that is required by the tumor is kind of a paradigm shift that will have a synergetic effect” in treating this type of cancer, he says.
