Neurons can form a brain tumor

Brain tumors: "Gliomas are incurable"

Dr. Synowitz, as a neurosurgeon, you deal with a special group of brain tumors, the gliomas. First of all, what are gliomas?

Michael Synowitz: Gliomas are a group of brain tumors. As far as we know today, they have their origin in the precursor cells of the glial cells, which form the supporting and nutrient tissue of the brain. A glioma can be classified according to which of the various types of glial cells the tumor is most similar in terms of tissue technology. There are, for example, the astrocytomas, which have their origin in the astrocytes. There are also oligodendrogliomas, which are similar to oligodendrocytes in terms of tissue technology. Gliomas can also be classified according to their prognostic course: there are high-grade and low-grade gliomas, with high-grade tumors being associated with a shorter survival time. My colleagues and I focus our research on high-grade gliomas such as glioblastomas.

What is so special about glioblastomas?
Glioblastomas are the most common malignant tumors of the central nervous system. They make up almost half of all gliomas. The glioblastoma is a very heterogeneous tumor, characterized by the evidence of pathological blood vessels. The tumor cells have a high tendency to spread and migrate through the brain. Glioblastomas can arise completely new or through progressive differentiation from less malignant astrocytomas.

Let's go back to gliomas in general. What are the symptoms of gliomas?
Inflammation, bleeding or brain tumors: they all take up space in the brain and can lead to the same clinical symptoms in the patient: headache, dizziness or seizures. The symptoms of gliomas also depend, among other things, on which area of ​​the central nervous system is affected. So the problem is: There are no specific symptoms for a brain tumor. It is therefore not possible to tell from the symptoms which illness the patient has. Glioblastomas in particular and so-called anaplastic astrocytomas, another malignant glioma, are very invasive: the cells begin to migrate to the surrounding areas of the brain very early. There is then a risk that they will continue to grow and form new flocks. Ultimately, this is what makes treatment so difficult. You are not dealing with a local disease that is limited to a certain area.

How do you diagnose a glioma like glioblastoma?
With the help of magnetic resonance tomography, we can take contrast medium images. Disturbances of the blood-brain barrier can be seen here, which can be seen in the area of ​​the suspected tumor area: The blood-brain barrier, which normally separates the bloodstream from the brain, is lifted and the contrast agent can travel from the blood to the brain diffuse. In the fine tissue there is a disintegration of cells and an increased formation of new blood vessels.

What do we know so far about the causes of gliomas?

The current doctrine is that there are niches in the brain where neural stem cells are present well into adulthood. These stem cells have the ability to divide and thus multiply without differentiating. It is assumed that this now leads to malfunctions. Some of them become “tumor stem cells”, that is, stem cells that cause tumors. They can continue to divide and thus multiply. However, unlike healthy stem cells, they lack certain safeguarding mechanisms. Healthy cells know that after a certain point - when there is no longer any need - they no longer have to divide. The diseased cells have lost this knowledge and divide in an uncontrolled manner. Presumably, gliomas come from such stem cells. Overall, however, different cell types seem to be involved in the individual gliomas.

What role do genes play?

Most gliomas occur with no apparent family history. The predisposition to gliomas is not inherited, but the tumors are caused by mutations. There are a number of known mutations, such as changes in a gene for a growth factor. This mutation ensures that cells divide more than normal.

Which glioma risk factors are known?
Little is known about the risk factors for gliomas. For a while it was believed that electromagnetic radiation, such as cell phone radiation, could play a negative role. However, large studies have not been able to provide definitive evidence for it or against it. We know very well from other types of tumors that ionizing radiation can lead to changes at the chromosomal level. It was found that the survivors of the atomic bombs dropped on Hiroshima and Nagasaki 10 or 15 years later developed increasingly tumors. Since we know little about the risk factors, early detection is unfortunately not yet possible.

What does the treatment look like now?
In the case of glioblastomas, the removal of the malignant tissue is the first step. One tries, of course, to remove the tumor as completely as possible. But that's a big challenge. During the operation in particular, it is difficult to see where the tumor ends and where healthy tissue begins. There is no smooth edge like there is with a sphere, but a flowing transition. As a result, some cells of the tumor almost inevitably remain in the brain. This is followed by irradiation of the enlarged tumor regions and chemotherapy. A recent study showed that such a combined treatment allows for longer survival times. So this is the gold standard that has been agreed upon.

And what do you do if the tumor comes back?
When the tumor comes back, but also when treating low-grade tumors or anaplastic astrocytomas, the choice of treatment becomes more difficult. It is then much more difficult to distinguish between imaging changes caused by chemotherapy and radiation therapy and imaging suspicion of new tumor growth. There are many discussions here about the best possible treatment and attempts are currently being made to develop guidelines, i.e. treatment recommendations without any binding effect on doctors.

What is the prognosis for gliomas with appropriate treatment?

Gliomas are incurable. The average survival time for high-grade glioblastoma is 15 months from the time of diagnosis; without treatment it would be about three months. But there is a wide range. More than five years after the diagnosis was made, around five percent of patients with glioblastoma are still alive. The prospects are better for low-grade gliomas: around 80 percent of patients with oligodendroglioma live longer than five years.

Does basic research give rise to hope for new therapies?
In recent years, my colleagues and I have been able to show that gliomas can also activate the brain's own stem cells in the stem cell niches. These stem cells differ from the degenerate tumor stem cells: They migrate to the tumor, recognize it and release messenger substances there. In a sense, the messenger substances tell the tumor stem cells that they should develop into a certain differentiated cell. This means that they lose one of their main characteristics, namely being able to divide in an uncontrolled manner. With increasing age, however, stem cells seem to lose the ability to migrate to tumors in the brain. This means that the brain also loses its ability to react to tumor diseases. This could also explain why many gliomas only appear after the age of 60. By this point the brain loses its ability to reproduce stem cells.

How could a therapy look like on this basis?
In the animal model of old animals we were able to restore the situation to a certain extent as we did with young animals by giving them stem cells. The tumors then regressed.

And what about humans?
In humans, the idea is to regenerate the stem cell potential of older people so that it resembles that of young people. To do this, however, we still have to conduct clinical studies.

Dr. Synowitz, thank you for the interview.