For the first time, researchers at Stanford University (CA, USA) have demonstrated that high-grade gliomas might integrate into the brain’s wiring.
According to the team, high-grade gliomas form synapses that hijack electrical signals from healthy nerve cells to drive their own growth. In addition to this, interrupting these signals with an existing anti-epilepsy drug was demonstrated to greatly reduce the cancers’ growth in human tumors in mice. These findings have been published in Nature.
How do high-grade gliomas hijack nerve cells?
Within the study, the investigators determined that high-grade gliomas form synapses with healthy neurons, which can enable electrical signals to be transmitted to the cancerous tissue. The tumors were also reported to contain gap junctions. Together, these connections would allow electrical signals from healthy neurons to be conducted into and amplified within the tumors.
Previous research conducted by Monje’s team have indicated that high-grade gliomas use normal brain activity to drive their growth. To understand this further, the team first analyzed the gene expression of thousands of individual cancer cells biopsied from newly diagnosed glioma patients. They revealed that the cancer cells strongly increased the expression of genes that are involved in forming synapses.
Electron microscopy was then utilized to demonstrate that structures resembling synapses exist between neurons and glioma cells. Thus, to confirm that these synapses do connect healthy neurons and malignant glioma cells, the investigators examined mice that had human glioma cells implanted into their brains. Once the glioma tumors were established, the team were able to use antibodies and fluorescent markers expressed by the cancer cells to confirm the synapses. “We saw very clear neuron-to-glioma synaptic structures,” stated Monje.
Additionally, to confirm that gap junctions existed between the tumor cells and mediated their electrical coupling, the researchers used a dye to visualize the gap-junction-connected cells and used drugs capable of blocking gap junctions. They also measured changes in calcium levels to confirm that the tumor cells were electrically coupled via these gap junctions.
“The live calcium imaging made it strikingly clear that this cancer is an electrically active tissue. It was startling to see that in cancer tissue,” commented lead author, Humsa Venkatesh (Stanford University).
Potential drug therapies
Using optogenetic techniques, the team demonstrated that increasing electrical signals into the tumors caused more tumor growth. Furthermore, this proliferation was largely prevented when glioma cells expressed a gene that blocked transmission of the electrical signals.
In addition to this, the team noted that existing drugs that block electrical currents also reduced growth of high-grade gliomas. Perampanal, which is a seizure medication that blocks activity of neurotransmitter receptors on the receiving end of a synapse, reduced proliferation of pediatric gliomas implanted into mice by 50%. On the other hand, meclofenamate, which is a drug that blocks the action of gap junctions, resulted in a similar decrease in tumor proflieration.
In the future, Monje’s team plan to continue investigating whether blocking electrical signaling within tumors could help people with high-grade gliomas. She concluded: “It’s a really hopeful new direction, and as a clinician I’m quite excited about it.”
Sources: Venkatesh HS, Morishita W, Geraghty AC et al. Electrical and synaptic integration of glioma into neural circuits. Nature doi:10.1038/s41586-019-1563-y (2019) (Epub ahead of print); http://med.stanford.edu/news/all-news/2019/09/brain-tumors-form-synapses-with-healthy-neurons.html
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