The Sheer Nerve of Cancer: Conversations Amongst Glioma and the Brain

Reading time: 5 minutes

Anthony Tao

The science of the brain has made strides since the 17th century when French philosopher Renes Descartes postulated that nerves communicate by pushing air through tiny tubes. Over a century later, it was biologist Luigi Galvani who, by electrocuting frogs, suggested that neurons talk not through air, but through electricity. Over the past few centuries, neuroscientists have better dissected the cellular and molecular underpinnings of the neural communication that underlies our thoughts, memories, and behaviors.

We now know that to communicate, neurons push electrical impulses along axons, which, similar to telephone wires, direct the electrical signal to other neurons. These axons contact other neurons through tiny interfaces called synapses. When an electrical signal reaches a synapse, molecules known as neurotransmitters are released. These neurotransmitters jump across the synapse and cause the recipient neuron to propagate the electrical signal. This is the fundamental building block of how our brain operates and it occurs with microsecond timing at nanometric scales.

A cancer, on the other hand, is not a brain. They do not form axons, they do not communicate through electricity, and they do not form synapses with each other. But, in more ways than one, it may seem like cancers can think, learn, and behave. They can adapt to their environment in incredibly versatile ways and travel to different areas of the body, all with the implicit purpose of survival. Of course, these behaviors are not typically mediated through neurons.

However, a group of researchers at Stanford University led by Michelle Monje have made several discoveries in the past decade showing that a specific type of brain cancer ‒ gliomas ‒ may access similar mechanisms used in neuronal communication to help with their cancer formation.

Neuronal activity can promote gliomas

In a paper published in 2015, the group posed a simple question: Does the electrical activity among neurons affect glioma? To answer this question, scientists modeled these brain tumors by grafting patient glioma cells into a mouse brain. They found that stimulating electrical activity in the mouse neurons led to better growth of the grafted cancers. They further identified a protein called neuroligin-3 as the mediator of these pro-tumor effects. These findings show that cancers in the brain do not simply grow on their own volition, but can be influenced by the activity of surrounding neurons.

However, it was still uncertain whether such effects required the formation of synapses between neurons and glioma cells.

Neurons can form synapses with glioma

In a 2019 publication, the researchers performed electron microscopy, a technique that allows visualization of nanoscopic structures such as synapses. Surprisingly, they saw that neurons can indeed form synapses on a few glioma cells.

To determine whether through these synapses, neurons can induce electrical impulses in gliomas, the scientists turned to a technique called patch-clamping, which allows for the measurement of electrical activity within single cells. Specifically, the researchers grafted gliomas into a mouse brain and electrically stimulated neurons within that brain. Excitingly, they found that neuronal activity can induce electrical activity in gliomas, proving that these neuron-to-glioma synapses were indeed functional. Furthermore, this increase in electrical activity within the glioma cell appeared to fuel growth of the tumor.

Overall, these findings show that when neurons talk through synapses, gliomas can listen.

Learning with Glioma

In the 1990s, one of the most exciting breakthroughs in the field of learning was spearheaded by Eric Kandel using a type of sea slug known as Aplysia. His work found that learning is mediated by changes at the synapse ‒ changes such as the formation of new synapses, the pruning of old ones, or the strengthening of individual synapses. This is known as synaptic plasticity.

In a recent publication, Monje’s research group wanted to know if these neuron-glioma synapses they had discovered can also exhibit plasticity. They focused on a signaling molecule known as BDNF, which is known to promote synaptic strength. As they had previously shown, neuronal stimulation promotes proliferation of gliomas grafted in mouse brains. However, when they removed BDNF from these neurons, this pro-glioma effect was reduced.

Looking deeper into the mechanism, the researchers found that when glioma were directly fed BDNF, the neuron-to-glioma synapses induced even stronger electrical activity in the cancer cells. Through electron microscopy, the researchers also found that BDNF could increase the number of neuron-to-glioma synapses. 

Together, these findings demonstrate that gliomas are capable of synaptic plasticity and that this plasticity is partly mediated by BDNF.

Glioma and the brain

Overall, the researchers led by Monje revealed how glioma can hijack the communication methods leveraged by neurons. They showed that neurons in the brain can secrete tumor-promoting neuroligin-3 and form synapses to directly communicate with gliomas ‒ synapses which, through BDNF, can undergo plasticity.

These findings provide tremendous insight into how brain activity can influence the growth of glioma. This can possibly explain why gliomas set up shop in certain areas of the brain, since different brain regions can have different degrees of electrical activity. Importantly, the fact that the survival of these gliomas partly rely on their conversations with neurons suggests therapeutic potential. Of course, it may prove difficult to clinically disrupt glioma synapses without impairing normal brain activity. Either way, these discoveries show that perhaps it’s not too hyperbolic to say that cancer can have a mind of its own. 

Edited by Emily Chan

References

1. Venkatesh, H. S. et al. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. Cell 161, 803–816 (2015).
2. Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).
3. Taylor, K. R. et al. Glioma synapses recruit mechanisms of adaptive plasticity. Nature 623, 366–374 (2023).