An innovative method “starves” glioblastoma, a currently incurable type of cancer
Pioneering research at Tel Aviv University led by Dr. Lior Mayo has succeeded in eradicating glioblastoma, a deadly form of brain cancer. Researchers found two important mechanisms in the brain that promote tumor growth and survival: One protects cancer cells from the immune system, while the other provides the energy needed for rapid tumor growth. The research found that astrocytes, which are brain cells, regulate both modes and that when they disappear, the tumor cells die and are eliminated.
Glioblastoma is an extremely aggressive and aggressive brain cancer for which there is no known effective treatment. Tumor cells are very resistant to all known treatments and, unfortunately, the life expectancy of patients has not increased significantly over the past 50 years. This discovery provides a promising basis for the development of effective drugs to treat glioblastoma and other types of brain tumors.
It is important to approach the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, the focus is on the tissue that surrounds the tumor cells. In particular, astrocytes, an important class of brain cells that support normal brain function, were discovered about 200 years ago and named for their star shape. In the last decade, the various functions of astrocytes that reduce or exacerbate various brain diseases have been discovered. Under the microscope, activated astrocytes were found to surround the glioblastoma tumor. From this observation, it was a question of investigating the role of astrocytes in glioblastoma tumor development.
Using an animal model in which they could eliminate activated astrocytes around the tumor, the researchers found that, in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4–5 weeks. By specifically eliminating astrocytes near the tumor, a spectacular result was produced: the cancer disappeared within a few days and all treated animals survived. Furthermore, even after discontinuation of treatment, most animals survived and, in most cases, no relapse occurred, indicating that astrocytes are essential for tumor progression and survival.
Therefore, the next step was to study how astrocytes convert from cells that support the growth of malignant tumors into cells that support normal brain activity.
To answer this question, the researchers compared gene expression in astrocytes isolated from healthy brain and glioblastoma tumors. They found two main differences, thus identifying changes in astrocytes when exposed to glioblastoma.
The first changes occurred in the immune response to glioblastoma. Up to 40% of the tumor mass comprises immune cells, mostly macrophages recruited from the blood or the brain itself. In addition, astrocytes can send signals calling immune cells to sites in the brain that need protection. In this study, astrocytes were found to fulfill this function in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, astrocytes “convince” them to “switch sides” and support the tumor rather than attack it.
The second transformation through which astrocytes support glioblastoma is through the production and transfer of cholesterol to tumor cells. Malignant glioblastoma cells divide rapidly, a process that requires a great deal of energy. Because the blood-brain barrier prevents them from accessing energy sources in the blood, they must obtain it from cholesterol produced in the brain, specifically in the astrocytic “cholesterol factory”, which normally supplies energy to neurons and other brain cells. supplies. The astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, since the tumor depends on this cholesterol as its main source of energy, removing this supply will starve the tumor.
Next, the researchers modified astrocytes near the tumors so that they stopped expressing a specific protein that transports cholesterol (ABCA1), thus preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: Without access to the cholesterol produced by astrocytes, the tumor was essentially “starved to death” within a few days. These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are in line with the researchers’ starvation hypothesis.
This work sheds new light on the role of the blood–brain barrier in the treatment of brain diseases. The general 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, this blockage makes it difficult for drugs to reach the brain and is considered a barrier to treatment. These findings suggest that, at least in the specific case of glioblastoma, the blood–brain barrier may be beneficial for future treatments, as it poses a unique vulnerability: the dependence of the tumor on cholesterol produced by the brain.
Currently, tools are available to remove astrocytes surrounding tumors in animal models, but not in humans. The challenge now is to develop drugs that target specific processes in astrocytes that promote tumor growth in humans.
But you can see the light at the end of the tunnel.