25 September 2017

Brain cancer: a new target

Neuroscientists have found a new way to treat malignant brain tumors

Anna Obraztsova, N+1

Neuroscientists from Stanford University found that the protein neuroligin-3 is necessary for the growth of high-grade brain tumors. They also found that the ADAM10 protein leads to its d-active form, the inhibition of which can become the basis for the therapy of such diseases. The work was published in the journal Nature (Venkatesh et al., Targeting neuronal activity-regulated neuroligin-3 dependence in high-grade glioma).

Gliomas of a high degree of malignancy are a number of brain tumors that originate from glial cells of the nervous system (auxiliary cells for neurons) and are characterized by a high growth rate. Surgically, such a tumor is difficult to remove, so the mortality rate is very high, and the search for chemical treatments is especially important.

In earlier studies, it was shown that the release of neurons of the neuroligin-3 protein promotes the division of tumor cells. This protein is involved in the formation of contacts between neurons. Initially, it is synthesized in cells in an inactive form, which is embedded in the cell membrane. Then the part of the protein that protrudes outside the cell is split off and, in fact, performs the functions of a neuroligin. Which protein produces the cleavage of the membrane form has so far remained unknown.

To study the effect of neroligin-3 on the development of gliomas, the authors used cell cultures from these tumors. The cells were transplanted into mice of two lines – the first has a normal neuroligin-3 gene, and the second is non–functional, from which the protein is not produced. It turned out that in the absence of neuroligin-3 in mice, tumors almost do not grow. At the same time, in such mice, the level of other neuroligins is increased (this is considered a compensating effect), which emphasizes the role of neuroligin-3.

Next, the scientists decided to find out which protein cleaves neuroligin-3. Using a program using machine learning algorithms, they searched among known proteases (enzymes that cleave proteins), and found those that may be specific to the extracellular part of neuroligin-3. Among them was the ADAM10 protein, which cleaves neuroligin-1. The authors of the work inhibited ADAM10 in tumor cells and measured the concentration of cleaved neuroligin-3 in the medium on which they were grown. It turned out that the concentration was reduced, which confirms the hypothesis about the role of ADAM10.

This study shows that by inhibiting ADAM10 protease, it is possible to reduce the amount of neuroligin-3, and thus stop the growth of malignant tumors. For a month, the scientists injected one of the inhibitors into mice with transplanted tumor cells. The substance passed through the hemato-encephalic barrier, and tumor growth decreased significantly. 

In addition to medications, methods of visualizing tumor boundaries are being actively developed, which will help make surgical removal more successful. Recently, quantum dots glowing under the influence of infrared radiation have been used to mark brain tumors in mice. In another work, mass spectrometry was proposed to determine the boundaries of the tumor during surgery.

Portal "Eternal youth" http://vechnayamolodost.ru  25.09.2017

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