A new target in the battle against deadly brain tumors

Mutations that could potentially cause cancer happen all the time in our cells, but many seem to be blocked by natural defenses against the disease. These protective mechanisms might provide a starting point for the development of potent new therapies; unfortunately, they have been elusive.

But a new study from Helmut Kettenmann's group at the MDC reveals a mechanism that helps the body fight one of the deadliest forms of brain cancer: high-grade astrocytoma (HGA). Rainer Glass, a former postdoctoral fellow in Helmut's lab (and now professor at the University of Munich, LMU), and his colleagues show that stem cells in the brain called neuronal precursor cells (NPCs) are attracted to HGA cells. When they draw near, they release factors that cause the tumor cells to self-destruct. The study, published in the August edition of Nature Medicine, suggests a completely new approach toward a disease that has stubbornly resisted treatment and is nearly always fatal.

The new study shows that when neural precursor cells (green) are attracted to high-grade astrocytomas, they release factors called endovanilloids that trigger a self-destruct mechanism in the tumor cells.

"High-grade gliomas are a type of cancer with an extremely poor prognosis," Helmut says. "A patient's average survival time after diagnosis is typically about a year and there are almost no five-year survivors. Moreover, there has been essentially no progress in finding cures over the past 30 years, despite attempts to treat HGAs with radiotherapy, chemotherapy, and surgery."

For many years Helmut's group and other labs have observed that neural precursor cells (NPCs) are attracted to tumor cells during the development of HGAs. Researchers suspected that NPCs release factors that cause the tumor cells to die. But no one knew precisely which factors were released, or how they affected the tumors.

Some of those questions have been clarified in a study by Rainer, Kristin Stock, Michael Synowitz, Jitender Kumar, and other members of Helmut's group. The scientists demonstrated that NPCs release specific fat molecules called endovanilloids. These molecules dock onto a protein called TRVP1, which appears in high quantities on the surfaces of tumor cells. The endovanilloids then activate a signal in the target cell that causes it to die.

"What we've known about TRVP1 comes from a completely different context – it's found in the nerves that sense pain," Helmut says. "It is activated by capsaicin, the active component in hot chili peppers. But until now it has not been considered a player in glioma biology."

Why don't adults enjoy the protection of endovanilloids? One factor might be a natural drop in the number of NPCs as a person ages – they are primarily needed as the brain grows and matures in infants and children. Their presence and functions in the adult brain have yet to be established. But even without them, Helmut says, it may be possible to imitate the way they affect TRVP1 and tumor growth.

Discovering this mechanism required experiments ranging from the test tube to mice and an investigation of tissues obtained from human cancer patients. First, the scientists exposed tumor cells grown in lab cultures to a mixture of molecules released by NPCs. This method allowed them to home in on endovanilloids; other molecules released by the cells didn't have anti-tumor effects.

It also revealed what happens when endovanilloids dock onto TRVP1: they trigger a self-destruct mechanism in the tumor cells. Encounters between external molecules and cellular receptors like TRVP1 often set off a cascade of chemical signaling within the cell. Information is passed from one molecule to the next, eventually leading to the activation of new genes. In this case, the study established that the message is received and then passed along by a protein called ATF3 which changes the cell's pattern of gene activation. This tells the cancer cell that something is wrong and it should self-destruct.

The scientists also discovered that the endovanilloids trigger a biochemical mechanism called the endoplasmic reticulum-stress pathway. The endoplasmic reticulum (ER) is a labyrinthine structure in cells made of membranes which plays an important role in the production of new proteins. Defects in the ER may cause it to accumulate enormous amounts of molecules and retain them, instead of releasing them. The structure swells up and eventually the cell dies. Under the electron microscope, the scientists observed such bloated ER structures in tumor cells from the tissues of humans, mice, and rats.

Studies in the test tube and mice showed that blocking endovanilloids removed the anti-tumor effects of the stem cells. This could be done either by breaking down the fat molecules themselves, by removing TRPV1 from the tumor cells, or blocking the signal that was generated by their interaction. In all of these cases, the cells failed to receive a signal to die, and even the presence of NPCs failed to protect an organism from aggressive tumors.

"This has important implications for the development of new therapies against high-grade gliomas," Helmut says. "When we treated older mice with artificial endovanilloids, they responded like young mice. Even when these mice had low numbers of NPCs, we saw an increase in the biochemical pathway stimulated by TRPV1 and a significant increase in the animals' survival."

Previous work on TRPV1 in its other context – pain reception – had identified a drug called Arvanil that activates the receptor. When the scientists applied it to mice with aggressive gliomas, the drug strongly reduced tumor growth.

"While Arvanil can't be used in humans due to side effects," Helmut says, "the studies in mice establish a proof of principle. Namely, that it makes sense to develop and test novel agents that activate TRPV1. They might become a crucial new tool in fighting a type of tumor that has been resistant to all the options for treatment that are currently available."

- Russ Hodge