An enzyme makes brain tumors dangerous

Scientists from the German Cancer Research Center (DKFZ) identified an enzyme that is responsible for the dangerous stem cell properties of glioblastoma, which represents a possible "Achilles tendon" in which the cells are vulnerable.

With a high GDP-1 expression, comes an unfortunate prognosis

If brain tumors return after therapy, this is due to cancer stem cells that were not affected by the treatment. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) were looking for characteristic proteins that characterize brain tumor stem cells. They identified an enzyme that is responsible for the dangerous stem cell properties of glioblastoma, which represents a possible "Achilles tendon" that makes the cells are vulnerable.

In many types of cancer, the treatments act exclusively on the rapidly dividing cancer cells that make up the large mass of a tumor. The stem cells of the tumor, on the other hand, hardly divide and are resistant to chemotherapy and radiation. Worse still, they are activated by the treatments and are then responsible for the tumor returning. This applies in particular to glioblastoma, the most aggressive of all brain tumors.

"The only way to prevent glioblastoma from relapsing after treatment would be a therapy that is effective against the brain tumor stem cells," said Haikun Liu from the German Cancer Research Centre (German acronym: DKFZ). "To do this, however, we would have to know molecular target structures that are specific to these cancer stem cells - so that the therapy does not damage healthy cells. But the problem is that brain tumor stem cells and the stem cells of the healthy brain share many molecular characteristics and properties."

Searching for suitable target structures

Among the proteins produced in cancer stem cells but not in brain stem cells, an enzyme of energy metabolism appeared to be of particular interest: the glycerol-3-phosphate dehydrogenase 1 (GPD1), produced by cancer cells, did not divide and occurred mainly on the so-called invasion front, where the tumor grows into healthy brain tissue. Very early on, about two weeks after the onset of cancer development, the researchers were able to detect GPD1 production in the growing tumor.

The researchers treated mice with the standard chemotherapeutic agent temozolomide and analyzed the tumors at different points in time after the end of the therapy. During the treatment, the GPD1-producing cells showed no division activity and remained in the sleep state characteristic of stem cells. But they awoke with the beginning of the relapse - a strong indication that they are responsible for the return of the tumor. If GPD1 was switched off by genetic methods in the tumor stem cells of mice, the animals survived longer.

High GPD-1 levels, unfavorable prognosis

Is GPD1 also responsible for the dangerous stem cell properties in human glioblastomas? A database analysis of tumors showed that, in glioblastoma patients, a high GPD1 production correlates with an unfavorable prognosis. High GPD1 levels are also associated with an unfavorable course in other types of cancer, such as renal cell carcinoma.

As already observed in mice, GPD1-producing cells were found mainly on the invasion front in tissue sections of human brain tumors. Cell lines cultivated from glioblastomas, whose GPD-1 had been switched off by the researchers, no longer grew into "mini tumors" in the culture dish - and thus lost a typical stem cell ability.

"This work is a first step towards identifying protein markers that characterize sleeping brain tumor stem cells and investigating their role in tumor biology," said Liu. "We have discovered so many interesting properties of GPD1 that we will now further investigate the enzyme as a target structure for possible therapies.