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Summary: A new method targeting the astrocytes surrounding glioblastoma brain cancer eliminates tumor cells and prolongs lifespan in animal models.
Source: Tel Aviv University
A landmark study at Tel Aviv University has effectively eradicated glioblastoma, a highly deadly type of brain tumor.
The researchers achieved the result using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other protects them from the immune system needed for rapid tumor growth supplies energy.
The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. Student Rita Perelroizen, under the direction of Dr. Lior Mayo from the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin from the National Institutes of Health (NIH) in the USA
The paper was published in the journal Brain and has been highlighted with special comments.
The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain tumor for which there is no known effective treatment. The tumor cells are very resistant to all known therapies, and unfortunately the life expectancy of the patients has not increased significantly in the last 50 years.
“Our results provide a promising basis for the development of effective drugs to treat glioblastoma and other types of brain tumors.”
dr Mayo says, “Here we approached the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, which is the tissue that surrounds the tumor cells. In particular, we examined astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their star-shaped shape.
“Over the past decade, research by us and others has revealed additional astrocyte functions that either alleviate or aggravate various brain disorders. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth.”
Using an animal model in which they could eliminate active 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.
Using a unique method to target and eliminate astrocytes near the tumor, they observed a dramatic result: the cancer disappeared within a few days, and all treated animals survived. In addition, most of the animals survived even after the treatment was discontinued.
dr Mayo says: “In the absence of astrocytes, the tumor rapidly disappeared and in most cases there was no recurrence – suggesting that astrocytes are essential for tumor progression and survival.” So we investigated the underlying mechanisms: how do astrocytes transform from cells that support normal brain activity into cells that support the growth of malignant tumors?”
To answer these questions, the researchers compared gene expression in astrocytes isolated from healthy brains and from glioblastoma tumors.
They found two main differences – thereby identifying the changes astrocytes undergo when exposed to glioblastoma. The first change concerned the immune response to glioblastoma.
“The tumor mass contains up to 40% immune cells – mostly macrophages that are recruited from the blood or the brain itself. In addition, astrocytes can send signals that call immune cells to sites in the brain that need protection.
“In this study, we found that astrocytes continue to serve this role in glioblastoma tumors as well. However, once the summoned immune cells reach the tumor, the astrocytes “persuade” them to “switch sides” and support the tumor instead of attacking it.
“In particular, we found that the astrocytes alter the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and facilitating its growth,” says Dr. mayo
The second change by which astrocytes support glioblastoma is by modulating their access to energy – via the production and transfer of cholesterol to the tumor cells.
dr Mayo: “The malignant glioblastoma cells divide quickly, a process that requires a lot of energy. Because the blood-brain barrier blocks their access to sources of energy in the blood, they must obtain this energy from the cholesterol produced in the brain itself—namely, in the astrocyte “cholesterol factory,” which normally fuels neurons and other brain cells.
“We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and deliver it to the cancer cells. Therefore, we hypothesized that since the tumor depends on this cholesterol as its main energy source, eliminating this supply will starve the tumor.”
Next, the researchers manipulated the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor.
Once again, the results were dramatic: Without access to the cholesterol produced by astrocytes, the tumor essentially “starved” in just a few days.
These remarkable results were obtained in both animal models and glioblastoma samples from human patients, and are consistent with the researchers’ starvation hypothesis.
dr Mayo notes, “This work sheds new light on the role of the blood-brain barrier in the treatment of brain disorders. 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, this barrier makes it difficult to deliver drugs to the brain and is seen as an obstacle to treatment.
“Our results suggest that the blood-brain barrier could be beneficial for future treatments, at least in the specific case of glioblastoma, as it creates a unique vulnerability – the tumor’s dependence on cholesterol produced in the brain. We believe this weakness can become a unique therapeutic opportunity.”
The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above.
The researchers explain: “In each patient, we examined the level of expression of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, supporting the concept that the identified genes and processes are important for glioblastoma patient survival.”
dr Mayo concludes: “Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans. The challenge now is to develop drugs that specifically target the processes in the astrocytes that promote tumor growth. Alternatively, existing drugs can be repurposed to inhibit the mechanisms identified in this study.
“We believe that the conceptual breakthroughs of this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for developing effective treatments for this deadly brain tumor and other types of brain tumors.”
About this brain cancer research news
Author: press office
Source: Tel Aviv University
Contact: Press Office – Tel Aviv University
Picture: The image is in the public domain
See also
Original research: Closed access.
“Astrocyte immune metabolism regulation of tumor microenvironment drives pathogenicity of glioblastoma” by Rita Perelroizen et al. Brain
Closed access.
“Forced but effective accomplices: How astrocytes drive glioblastoma progression” by Kai Murk et al. Brain
abstract
The immunometabolic regulation of the tumor microenvironment by astrocytes drives the pathogenicity of glioblastoma
Malignant brain tumors are the cause of disproportionate morbidity and mortality in cancer patients, an unfortunate statistic that has remained constant for decades. Despite significant advances in the molecular characterization of these tumors, targeting the cancer cells has not yet resulted in significant advances in treatment.
An alternative strategy is to target cells in the glioblastoma microenvironment, such as B. tumor-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain’s metabolic homeostasis to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood.
Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival.
Analysis of the tumor-associated astrocyte translatom revealed that astrocytes initiate transcription programs that shape the immune and metabolic compartments in the glioma microenvironment. In particular, their expression of CCL2 and CSF1 directs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype.
At the same time, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival and that targeting astrocytic cholesterol efflux via ABCA1 halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting glioblastoma’s non-oncogenic metabolic dependence on cholesterol.
These results suggest that targeting astrocytes’ immunometabolic signaling may be useful in the treatment of this uniformly fatal brain tumor.
abstract
Forced but effective accomplices: How astrocytes drive glioblastoma progression
Glioblastoma multiforme (GBM) is the most common and most malignant glioma in adults. Patients diagnosed with GBM face the grim prognosis of a median life expectancy of about 15 months.
As the tumor progresses, patients are likely to experience severe complications such as epileptic seizures, peritumoral edema, and intracranial hypertension.
The extreme aggressiveness of GBM is the result of several pathological features. For example, GBM spreads diffusely throughout the CNS, potentially evading surgical intervention.
When GBM makes its way through the parenchyma, it causes severe tissue damage and disrupts CNS functions. In addition, GBM effectively resists conventional radiation and chemotherapy.
