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The Warsaw Voice » The Polish Science Voice » November 28, 2013
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Defusing Malignant Brain Tumors
November 28, 2013   
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Cells of malignant brain tumors deceive a patient’s immune system so effectively that it starts working for them. But this can also work the other way: researchers from the Nencki Institute of Experimental Biology in Warsaw have found a way to deceive brain tumors and transform malignant gliomas into benign forms.

A research team led by Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw has developed a method—so far used only in animals—for converting malignant gliomas (brain tumors) into benign forms. Since the cells of benign gliomas are subdued and sometimes even eliminated by the host’s immune system, the chances of a sick animal surviving significantly increase. This novel research was funded by the Polish National Science Center.

The human nervous system, including the brain, is inhabited, besides neurons and glial cells, by microglial cells. They support the nervous system cells but also have important protective functions, “patrolling” the surroundings and eliminating damaged or unnecessary cells. They also fight foreign bacteria, viruses and tumorous cells. Unfortunately, sometimes the glia cells themselves become cancerous. This is how brain tumors called gliomas form. These can differ significantly with respect to their degree of malignancy. In benign variants, patients’ chances of survival are quite high, while in the case of malignant gliomas few patients are expected to live longer than a year.

In 2007, Kamińska’s team showed that malignant gliomas can “re-program” brain immune cells (microglia) to support tumor development instead of fighting it. The research to understand how the tumor deceives the host's immune system and forces the microglial cells to support and foster its growth has taken several years.

The results of other research groups showed that, in the case of breast cancer, the factor responsible for changing the behavior of tumor-infiltrating macrophages is the CSF1 protein, controlling the maturation of macrophages. Researchers from the Nencki institute asked whether a similar substance is not produced by the cells of malignant gliomas.

Studies conducted by Kamińska's team have shown that gliomas do not produce the CSF1 protein and that this protein does not significantly impact tumor development. However, the researchers managed to observe the production of a different protein from the same family, the CSF2 protein. In benign tumors, this protein was present in small amounts, while in malignant gliomas large amounts of it were discovered. Researchers from the Nencki institute decided to investigate whether this protein really influences tumor invasiveness. With the help of tools they developed, they turned off the gene responsible for the production of the CSF2 protein in glioma cells.

“We have observed that after turning off a single gene—the gene producing the CSF2 protein—the tumor cells stopped attracting the microglia and were not capable of converting these cells to support the tumor's development. As a result, the immune system started working as expected and the malignant tumor was transformed into a benign form. It did not disappear, but stopped growing," says Małgorzata Sielska, a Ph.D candidate from the Nencki institute.

The protein responsible for "re-programming" the anti-tumor response and for high invasiveness of gliomas is present only in cancerous cells and is practically absent from a healthy brain. Therefore researchers from the Nencki institute suspect that when the gene responsible for its production is turned off in the brain, it will affect only the tumor.

Research on taming malignant brain tumors and converting them into benign forms has been conducted on mouse glioma cells growing in the brains of experimental animals, and published in the Journal of Pathology. At the moment, Kamińska’s group is checking the effectiveness of this method in the cells of human malignant gliomas. Preliminary results confirm that silencing one gene in human glioma cells growing in mouse brains also stops the growth of the tumor. Developing tools to turn off this gene's expression, following the creation of appropriate carriers, will in the future open new possibilities for gene therapy in humans.

The findings have helped the Nencki researchers develop small molecules (short peptides) which interfere with binding the CSF2 protein (expressed by tumorous cells) to the appropriate receptors on microglial cells. This way the signal coming from tumorous cells gets blocked and the microglia is prevented from "re-programming" itself. The developed molecules, together with appropriate genetic tools, are covered by an international patent. At the moment, the researchers are working to bring about preclinical and clinical trials of this method.

The proposed solution holds great potential for therapies using small molecules—short peptides or, in the case of gene therapy, short RNA silencing gene expression.

Ribonucleic acid (RNA) molecules play a key role in transcribing genetic information, in the formation of proteins and in all cellular processes. By influencing the RNA molecules inside a cell, it is possible to heal various diseases.

Will this method really work? This will be determined by further experiments and tests. For the Nencki institute researchers it is important that the patented molecules target only one fragment of the signaling pathway, which functions between the cells of the malignant tumor and the microglia, thus guaranteeing that no other functions of the patient’s body are affected. Moreover, the discovery of such an important signaling pathway encourages scientists to search for ways of blocking it in other places, which could be technically more feasible.

“Our research above all aims to explain why and how tumors develop,” Kamińska says. “We conducted our research mostly on experimental models, mouse glioma cells or human glioma cells growing in mice. Therefore the road to developing drugs and therapies limiting the invasiveness of gliomas in humans is still very long. Luckily, we have already discovered the molecule that is worth targeting.”
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