Nature: the first discovery of synapses between gliomas and healthy neurons

September 24, 2019 / Biovalley BIOON/--- in a new study, researchers from Stanford University in the United States confirmed for the first time that severe brain cancer can be integrated into the brain's neural connections They found that brain tumors called high-grade gliomas synapse with healthy neurons, hijacking electrical signals from healthy neurons, thus promoting their own growth Experiments show that the use of existing antiepileptic drugs to destroy these electrical signals can greatly reduce the growth of human tumors in mice, which provides the first evidence for a new potential treatment of glioma The relevant research results were published online in the nature Journal on September 18, 2019, with the title of "electrical and synthetic integration of glioma into natural circuits" The corresponding author is Dr Michelle monje, associate professor of Neurology and neuroscience, Stanford University School of medicine The first author is Dr humsa Venkatesh, a postdoctoral researcher at Stanford University Picture from nature, 2019, DOI: 10.1038/s41586-019-1563-y "One of the deadliest aspects of high-grade gliomas is the proliferation of cancer cells into normal brain tissue, allowing the tumor to integrate with healthy brain tissue," said Michelle monje, associate professor of Neurology and neuroscience at Stanford University and co-author of the paper She added that the findings help explain why gliomas are so difficult to treat "This is a very subtle type of tumor They're actually integrated into the brain " Monje said it was "disturbing" to find that tumors connect themselves to the brain Still, she says she is optimistic about what this knowledge means for patients with glioma She said there are several drugs that can treat electrical signal disorders such as epilepsy, which may be useful for glioma "This discovery is really promising," she said We have previously neglected the whole aspect of the disease Now, we have a new way to explore and complement the existing treatment " How brain tumors grow this new study finds that high-grade gliomas form synapses with healthy neurons that transmit electrical signals to cancerous tissue These tumors also contain intercellular electrical connections called gap junctions These two types of connections allow electrical signals from healthy neurons to be transmitted to and amplified in tumors High grade gliomas include glioblastoma, a brain tumor seen in adults with a five-year survival rate of 5%; diffuse endogenic pontine gliomas, a brain tumor in children 5-year survival was less than 1%; and other high-grade gliomas were diagnosed, such as glioblastoma in children and diffuse midline gliomas in the spinal cord and thalamus Research published by monje and his team in 2015 and 2017 has shown that high-grade gliomas use normal brain activity to drive their growth To understand the mechanism, the researchers first analyzed the gene expression of thousands of cancer cells from newly diagnosed patients with glioma These cancer cells greatly increased the expression of genes involved in the formation of synapses The researchers then used electron microscopy, a technique that reveals tiny details of the anatomy of cells, and found synaptic like structures between neurons and glioma cells To confirm that these synapses do connect healthy neurons to malignant glioma cells, they studied human glioma cells transplanted into the mouse brain After glioma tumors formed, they used antibodies that bind to fluorescent markers expressed by these cancer cells to confirm that these synapses entered these cancer cells "We see very clearly the synaptic structure between neurons and glioma," monje said Using brain tissue from mice carrying human glioma, the researchers measured how electrical signals enter and travel through the tumor They recorded two types of electrical signals: transient signals lasting for 4 to 5 milliseconds, which are transmitted from healthy neurons to cancer cells through synaptic connections in the form of neurotransmitters; and continuous electrical signals lasting for one to two seconds, which reflect the current that potassium ions transmit when they pass through the membrane of tumor cells Potassium currents are caused by signals from neurons and amplified by connecting cancer cells to gap connections in the electrical coupling network The researchers also carried out experiments with dyes to visualize cells connected by gap junctions, and used drugs to block gap junctions to confirm that similar junctions exist between tumor cells and their electrical coupling Further experiments to measure the changes in calcium levels confirm that these tumor cells are electrically coupled by gap junctions "Real time calcium imaging clearly shows that this cancer is an electrically active tissue," Venkatesh said It's amazing to see this in cancer tissue " The researchers found that about 5-10% of glioma cells receive synaptic signals, and about 40% of glioma cells show potassium current amplified by gap connection for a long time, which makes half of glioma cells make some type of electrical response to signals from healthy neurons Potential pharmacotherapy in human patients and mice with human gliomas who had measured electrical activity in the brain prior to surgical removal of glioblastoma, these researchers observed that highly charged healthy neurons were located near the tumor, a finding that may help explain why gliomas are prone to seizures By using photogenetics, which relies on laser activation of cancer cells in mice transplanted with human glioma, the researchers confirmed that increasing electrical signals into the tumor can lead to more tumor growth When glioma cells express a gene that blocks the transmission of these electrical signals, it can largely prevent the proliferation of these tumors The new study found that current blockers also reduced the growth of high-grade gliomas An epileptic drug, perampanel, blocks the activity of neurotransmitter receptors on the synaptic receptor, reducing the proliferation of pediatric gliomas transplanted into mice by 50% Meclofenamate, a drug that blocks gap junction, can cause a similar decline in tumor proliferation The monje team plans to continue to study whether blocking electrical signals in tumors can help people with high-grade gliomas "This is a very promising new direction," she said As a clinician, I'm very excited about that " (bio Com) reference: 1 Humsa S Venkatesh et al Electrical and synthetic integration of glioma into natural circuits Nature, 2019, DOI: 10.1038/s41586-019-1563-y 2 Brain tumors form synapses with healthy neurons, study finds https://mediaexpress.com/news/2019-09-brain-tumors-synapses-health-circuits.html