Scientists have discovered that brain tumors integrate themselves with the brain’s healthy neuronal network to support their growth. Following this discovery, new brain tumor treatments are being developed which stunt tumor growth through preventing these connections with anti-epilepsy drugs.
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Intertwining with healthy tissue makes gliomas difficult to treat
Gliomas are notoriously difficult to treat, and the prognosis for all kinds of glioma is generally poor, with a five-year survival rate of 5% in glioblastoma, and a five-year survival rate of below 1% in diffuse intrinsic pontine glioma (a pediatric brain tumor).
While other areas of cancer research have seen great steps forward in terms of understanding how they develop and thrive, which has lead to innovations in improved and more varied treatment options, the effective treatment of gliomas has made little progress.
High-grade gliomas infuse through healthy brain tissue, making it difficult for scientists to conceive ways to remove them without damaging healthy cells.
This month, 3 studies were published in Nature that reveal a crucial piece of the puzzle to understanding how gliomas thrive in the brain. Through these three studies, a team at Stanford University School of Medicine has uncovered the mechanism that gliomas, and breast cancers, use to integrate themselves into the brain.
The tumors have been seen to attach themselves to the brains neuronal network, forming synapses with healthy neurons in order to commandeer their electrical impulses to help them to grow. In addition, it has been found that the tumors also develop gap junctions, or cell-to-cell electrical connections, which also stimulate their growth.
The three studies showed that these tumors spread and grow through the brain’s healthy tissue by hijacking neuronal connections.
Treatment through epilepsy drugs
The impact of these seminal findings is that scientists now have an avenue to explore for developing a new breed of treatments.
It is now understood that in addressing this synaptic and electrical integration into neural circuits, some headway may be made in preventing and even reducing tumor growth. Scientists are looking to epilepsy drugs as a place to start, as these drugs are specifically designed to treat electrical-signaling disorders of the brain.
While the results of the three studies provide a look into the very sinister nature of gliomas, it is being viewed positively because now there are clues towards how successful therapeutic approaches may be designed.
What we now know about how gliomas grow
In 2015, the first pieces of evidence began to emerge that showed high-grade gliomas stimulating their growth through normal brain activity.
The Stanford team looked into this relationship further and analyzed the gene expression of biopsied cancer cells from glioma patients. They found that genes involved in forming synapses were activated in the presence of the cancer cells.
Electron microscopy then revealed synapse-looking connections between neurons and glioma cells. Following this, malignant glioma cells were established in the brains of mice, and the presence of neuron-to-glioma synapses were confirmed as antibodies bound to fluorescent markers. The connections in the brains of these mice were then studied.
The research team found the existence of two kinds of signal:
The first was transmitted through neurotransmitter molecules across a synaptic junction from a healthy neuron to a cancer cell and lasted just four to five milliseconds.
The second was a signal lasting one to two seconds that was attributed to potassium ions crossing the tumor cells' membranes, signifying the existence of gap junctions connecting the tumors to the neural network. Finally, the team was also found breast-cancer cells behaving like neurons, demonstrating how breast cancer spreads into the brain.
Developing new treatments
The studies showed that increased activity of the electrical signals to the tumors increased their growth. Therefore, scientists can now work on developing treatments that reduce signaling in order to prevent growth.
It has already been seen that a seizure medication that prevents neurotransmitter receptor activity was able to reduce the growth rate of glioma in the mice by 50%. This is being seen as a positive new avenue for developing effective glioma treatments.
- Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. nature.com/articles/s41586-019-1564-x
- Electrical and synaptic integration of glioma into neural circuits. Nature. nature.com/articles/s41586-019-1563-y
- Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. nature.com/articles/s41586-019-1576-6