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Growing bad due to bad influences: here go guilty astrocytes hosing the cancer mass with cholesterol

Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma by combining existing molecules. The researchers achieved the outcome 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 supplies the energy required for rapid tumor growth. The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated. Astrocytes are major major brain cells that support normal brain function. Over the past decade, several research teams revealed additional astrocyte functions that either alleviate or aggravate various brain diseases.

Under the microscope scientists found that activated (technically defined “reactive”) astrocytes surrounded glioblastoma tumors, deeming that they could have some role in the tumor biology. 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. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived. Therefore, researchers investigated the underlying mechanisms: “how do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?” To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.

They found two main differences – thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma. The tumor mass includes up to 40% immune cells, mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, it has beeb found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it. Specifically, the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly, thereby protecting the tumor and facilitating its growth. The second change through which astrocytes support glioblastoma is by modulating their access to energy, via the production and transfer of cholesterol to the tumor cells.

The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources from blood glucose coming through the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself – namely in the astrocytes, which usually supplies energy to neurons and other brain cells. Well, this is exactly what reactive astrocytes do around the cancer mass: they increase the production of cholesterol and supply it to the cancer cells. Therefore, hypothesing that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor the researchers engineered the astrocytes near the tumor to stop expressing a specific cholesterol transporte (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially ‘starved’ to death in just a few days.

These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis. According to the authors, this work strenghtens the role of the blood-brain barrier in treating brain diseases. 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 event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. The findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability, i.e the tumor’s dependence on brain-produced cholesterol. And this weakness can translate into a unique therapeutic opportunity. The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above.

Leader of the study Dr. Mayo explained: “For each patient, we examined the expression levels 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, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients. 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 target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Perelroizen R et al. Brain. 2022 Sep; 145(9):3288-3307.

Cigliano L et al. Mol Cell Endocrinol. 2019; 486:25-33.

Kambach DM et al. Oncotarget. 2017; 8(9):14860-14875.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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