The brains of individuals with autism may shed light onto the physiological nature of one of the most common and most deadly forms of brain cancer. Researchers from the Johns Hopkins University School of Medicine have discovered that both autism and glioblastoma seem to have malfunctioning of the same protein: NHE9. Typically, we do not associate autism with brain cancer – they are two different conditions that are not normally linked together. Autism spectrum disorder is a range of complex neurodevelopment issues that are characterized by communication difficulties and impaired social behavior. This psychological disorder is not fatal and is never the direct cause of death in an individual. Certain types of brain cancers, such as glioblastoma, on the other hand, are extremely dangerous and often fatal. Glioblastoma specifically has a notoriously low survival rate of 10 percent five years after being diagnosed. However, researchers from the Johns Hopkins University School of Medicine have discovered a link between these two seemingly unrelated diseases. In a study published in the journal Nature Communications, the authors describe their work on intracellular transportation. Originally, the researchers had been studying the activity of endosomes, the cell’s main method of transportation (think cargo shipping). All human and animal cells use endosomes to transport newly created proteins to specific destinations in the cell and old proteins to be destroyed and recycled. The speed at which the endosomes travel is regulated by the acidity of the fluids inside of the endosome’s membrane. This in turn is mediated by the activity of proton “pumps” that pull protons into the endosomes and proton “leaks” that push protons out of the membrane. There is a delicate balance of activities to keep the acidity inside of the endosome constant. NHE9, the protein that the researchers were interested in, is a proton leak. In autism, NHE9 proteins are defective and do not let the protons efficiently leak out — the mutated protein essentially acts like a plug. With the buildup of protons, the fluids inside the endosome become more acidic, making them race to transport and destroy proteins, causing premature cell protein death. The researchers searched through patient databases to learn more about NHE9, and they discovered data showing that elevated levels of the proton leak are associated with resistance to traditional cancer treatment methods, such as radiation and chemotherapy, in glioblastoma patients. By examining brain tumors from several patients, they were able to discover that cells with high levels of NHE9 grew faster than cells with a lower level. Furthermore, the researchers found that cells with a higher level of NHE9 could travel faster when placed on a surface similar to that of a brain, suggesting a higher possibility for metastasis. They confirmed this hypothesis by transplanting tumor cells with either high or low levels of NHE9 into the brains of mice.
Based on previous research on autism, the researchers suggest that the glioblastoma cells would have endosomes with abnormal pHs. In fact, the endosomes in brain tumor cells are on the basic side — the NHE9 in brain cancer cells, in contrast to those in autism, are overexpressed, which causes the endosomes to leak out too many protons. Naturally, this would cause the transportation rate to decrease and result in the longevity of cancer-promoting proteins.
One of these proteins, as previous research has suggested, is EGFR. EGFR can be found on the cell membrane’s surface and sends out cancer-promoting signals. It also helps tumors become more robust, and more than half of those who suffer from glioblastoma have elevated levels of EGFR. Currently, there are drugs that target and deactivate this protein, but the success rate is not very high.
However, when researchers administered drugs that countered NHE proteins, as well as drugs that countered EGFR proteins, to lab-grown glioblastoma cells, they discovered that the cells were more readily killed, compared to cells that were only treated with EGFR-countering medication. This leads to the idea that drugs used to regulate NHE9 levels could also be used to combat brain cancer in patients.
These results are encouraging and suggest that targeting both the NHE and EGFR proteins could be a potential treatment for glioblastoma. However, this is only the first step in the long process of discovering a dependable cure — the researchers state that they are still five to 10 years away from testing possible clinical treatments in patients.
