A groundbreaking study by PhD student Rita Perelroizen, supervised by Dr. Lior Mayo of the School of Biomedicine and Cancer Research and the School of Neurosciences at Tel Aviv University, has succeeded for the first time in targeting glioblastoma cells, one of the most aggressive and invasive brain cancers, by inhibiting two critical mechanisms that control growth. and promote survival of these deadly tumors. These discoveries, which are already resonating in the medical world, provide a promising basis for the development of effective drugs to treat this currently untreated cancer, as well as other types of brain tumors.
The results of the study, conducted in collaboration with Prof. Eytan Ruppin of the Institutes of Health (NIH) in the United States, were published in the prestigious scientific journal Brain in which they were the subject of a scientific commentary by researchers at the Charité University Hospital in Berlin.
The tissues surrounding the tumor
“There is no long-term medical treatment for glioblastoma today,” explains Dr. mayo out. “It is resistant to all known therapies. The life expectancy of affected patients averages two months after the disease was discovered and has not changed in the past 50 years. We chose to tackle the challenge of this cancer from a new angle: instead of focusing on the tumor itself, we focused on its microenvironment, ie the tissues surrounding the tumor cell. More specifically, we focused on the study of cells called astrocytes, brain cells discovered about 200 years ago, whose name is derived from their star shape. These glial cells form the environment for neurons and are responsible for normal brain activity. Research over the past ten years has shown that they also have additional functions, including in various brain diseases, which reduce or exacerbate them. By observing glioblastoma cells under the microscope, we found that they were surrounded by astrocytes, and we wondered what role they played in the development of this cancer”.
To answer this question, the researchers used genetically modified mice, which allowed them to eliminate active astrocytes around the tumor. They then found that in the presence of astrocytes, the cancer was 100% lethal and all affected mice died within 4 to 5 weeks. On the other hand, when they allowed the astrocytes to disappear from the tumor’s environment, the result was spectacular: the cancer disappeared in a few days and all treated mice survived, most survived even after treatment was stopped.
“In the absence of astrocytes, the cancer disappeared and in most cases there was no relapse, indicating that astrocytes are essential for the progression and survival of the deadly tumor,” says Dr. mayo. “We therefore investigated the mechanisms underlying this phenomenon: how do astrocytes transform from cells that help normal brain activity into cells that promote the growth of malignant tumors? »
“Good” cells that become “bad”
The researchers then compared the gene expression of astrocytes from healthy brains and glioblastoma tumors, and found that astrocytes exposed to glioblastoma undergo two key changes. The first concerns the immune response to the tumor.
“The tumor mass comprises up to 40% of immune cells, mainly macrophage cells that are recruited from the blood or from the brain itself. In addition, astrocytes can send signals that call immune cells to parts of the brain that need protection. In this study, we found that in the presence of glioblastoma tumors, the astrocytes continue to play this role, but once the immune cells arrive at the tumor, they “persuade” them to “switch sides” and help the cancer rather than attack it. to fall . In particular, we found that astrocytes cause immune cells to secrete specific proteins that prevent other immune cells (lymphocytes) from attacking the tumor, in effect protecting and growing it,” explains Dr. mayo out.
The second change by which astrocytes help glioblastoma involves their access to energy, especially cholesterol. “Glioblastoma tumors require a lot of energy to grow, but the blood-brain barrier blocks their access to energy sources from the blood,” she explains. “They must therefore derive this energy from the cholesterol produced by the brain itself, in particular from the ‘cholesterol factory’ formed by the astrocytes, which generally supply energy to neurons and other brain cells. We found that the astrocytes surrounding the glioblastoma tumor increase their production of cholesterol to deliver it to cancer cells. Glioblastoma tumors therefore depend on this energy source for their survival. Therefore, we hypothesized that eliminating this stock would ‘starve’ the tumor.
The researchers therefore modified the astrocytes close to the tumor so that they no longer express a certain protein (ABCA1), which prevents them from releasing cholesterol into the tumor. Again, the results were spectacular: without access to the cholesterol produced by the astrocytes, the tumor is effectively ‘starved’ and disappears within a few days. These remarkable results obtained on mice have been verified on glioblastoma samples taken from human patients.
Overcoming the blood-brain barrier
“This work sheds new light on the role of the blood-brain barrier in the treatment of brain diseases,” notes Dr. May on. “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 case of brain disease, it makes the passage of drugs difficult and is therefore considered an obstacle to treatment.” Our results suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial, as it creates a tumor fragility that is completely dependent on the cholesterol produced by the brain itself. weakness can translate into exceptional therapeutic opportunity.”
In a next step, the researchers looked at databases of hundreds of glioblastoma patients and found a direct correlation between study results and patient survival time: “For each patient, we compared the survival time and expression level of genes associated with the two phenomena of transformation of astrocytes in contact with glioblastoma: neutralization of the immune response and cholesterol supply. We found that patients with low expression of these genes lived longer, leading to the conclusion that these genes are related to the survival of glioblastoma patients.”
“We currently have the tools to eliminate astrocytes around the tumor in mice, but not in humans. The challenge now is to develop drugs that inhibit the mechanisms identified in this study by which astrocytes promote tumor growth,” concludes Dr. Mayo. believe this study is a major breakthrough in the fight against glioblastoma and hope that our results will serve as a basis for developing effective treatments for this deadly brain cancer, which remains without effective treatment to date, and for other cancers. brain tumors”.
Source: French Friends of Tel Aviv University