Glioblastomas, the most common and most aggressive brain tumors, apparently arise from neural stem cells (NSCs) in the brain. Researchers are now beginning to understand the mechanisms of how NSCs, which are present in small quantities in the adult brain and which are responsible for the production of new neurons, give rise to tumor stem cells. A number of factors have been identified that regulate the NSCs and cause them to differentiate, as scientists from Italy and Germany reported at the Brain Tumor Meeting 2011 at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany. With these findings, they hope to identify targets for a more effective treatment of glioblastomas and other brain tumors.
New neurons derive from stem cells that reside in a niche of the brain known as the subventricular zone. Scientists have long suspected that the origin of glioblastomas is also found here. Glioblastomas consist of different cell types and their progenitor cells. Some time ago, researchers were also successful in isolating tumor stem cells from glioblastomas. These have the characteristics of stem cells, that is, they have the capability of self-renewal. This means that tumor stem cells constantly generate new tumors. Possibly this is the reason why tumors can recur despite treatment.
However, how does a stem cell, which the organism needs to generate new cells, turn into a tumor stem cell? “Tumor stem cells in the brain use several key regulators which normally control the generation of new neurons in the adult brain,” said Professor Angelo L. Vescovi (University of Milano-Bicocca, Italy) in Berlin. These include the ephrins, an important substance group of signaling molecules in the brain and their target molecules (receptors) on the stem cells, the Eph receptors, to which they bind. Both carry out diverse tasks in the brain, including the regulation of neuron regeneration.
As Professor Vescovi reported in Berlin, he and his colleagues mapped the genetic blueprint not only for the Eph receptors, but for their binding partners the ephrins as well – and this both in the glioblastoma tissue and in the tumor stem cells contained in this tissue. One receptor, EphA2, was highly overexpressed.
In first in vitro experiments, they succeeded in down-regulating the activity of this receptor. As a consequence, the tumor stem cells no longer had the capacity of self-renewal, thus drying up their ability to generate brain tumors. The tumor stem cells were not driven to apoptosis, that means they were still present, but they lost their characteristic as a tumor stem cell, a sort of cell reprogramming, which took away carcinogenicity.
In fact, when the down-regulation of the receptor was enforced in human gliomas growing in the brain of mice (using a system similar to those to be used in patients), the expansion of these lethal tumors was slowed quite significantly. “We have now applied for permission to initiate a phase I trial in humans and hope that by influencing such key regulators, new approaches to the treatment of glioblastoma can be developed,” said Professor Vescovi.
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Researchers Identify Key Molecule of Stem Cells in Human Glioblastoma Cells
Professor Günther Schütz of the German Cancer Research Center (DKFZ) in Heidelberg and Professor Peter Lichter (also DKFZ) recently identified a specific molecule on brain stem cells – the protein Tlx. It is a transcription factor which stimulates the activity of specific genes, inducing normal NSCs to migrate from their niche and develop into healthy neurons.
“However, if the stem cell produces too much of this protein it develops into a tumor cell,” Professor Schütz said at the Berlin meeting. He and his colleagues from the DKFZ were thus the first to provide evidence that glioblastomas can in fact arise from stem cells. If the researchers switched off Tlx in the brain stem cells, new neurons were no longer generated in the adult mice. If they induced the stem cells to produce too much Tlx, the stem cells developed into tumor cells. If they additionally switched off the protective protein p53, the cancer developed at an increased rate.
As Professor Schütz explained further in his presentation in Berlin-Buch, he and his colleagues were able to show that also human glioblastomas produce too much Tlx. At the same time, the genes encoding Tlx in these glioblastomas are amplified, i.e. they are present in many copies. As a result of this amplification process, the tumor cells produce even more Tlx.
Next, the researchers succeeded in elucidating the mechanism by which Tlx turns a NSC into a glioblastoma cell. They discovered that excess Tlx in the NSCs deactivates two genes, thus inducing these cells to secrete increased quantities of Tlx. This means that the NSC becomes a glioblastoma cell, losing its original characteristics and taking on a new identity: The former NSC has turned into a glial cell. Besides neurons, the glial cells are the second major group of cells in the brain. “This transformation,” Professor Schütz concluded, “may also explain why brain tumors have the identity of glial cells.”
Around 200 scientists from the U.S. and Europe participated in the two-day Brain Tumor Meeting 2011 at the Max Delbrück Communications Center (MDC.C), which ended Friday, June 17th. The organizers were Professor Helmut Kettenmann and Dr. Rainer Glaß of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Professor Peter Vajkoczy and Dr. Michael Synowitz (Charité – Universitätsmedizin Berlin) and Professor Jürgen Kiwit (Helios Klinikum Berlin-Buch).
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