Researchers are beginning to understand why certain brain cancers are so hard to stop.
Three studies published Wednesday in the journal Nature found that these deadly tumors integrate themselves into the brain's electrical network and then hijack signals from healthy nerve cells to fuel their own growth.
But the research offers hope as well. Scientists say the findings suggest that some brain tumors could be slowed with drugs that inhibit the activity of certain brain cells or that interrupt connections between tumor cells and healthy cells.
Two of the three studies, including Winkler's, looked at high-grade gliomas, which include glioblastoma, the cancer that killed Sen. John McCain in 2018.
"High-grade gliomas are really an intractable set of diseases, and we've made very little progress clinically in effectively treating these terrible brain cancers," says Dr. Michelle Monje, an associate professor of neurology and neurological sciences at Stanford University and an author of a second study.
In 2015, Monje was part of a team that found high-grade gliomas grew faster when the brain cells around them became more active.
Monje's team suspected that was because active neurons produce a substance that acts like fuel for gliomas. So the team placed human glioma tumors in the brains of mice that had been genetically altered so they couldn't produce this substance.
"There wasn't just a slowing in the tumor growth — there was a complete stagnation," Monje says. The study was published in 2017.
In people, though, Monje was pretty sure that high-grade gliomas were somehow causing healthy brain cells to become more active and produce more fuel. And she thought the cancer cells might be doing this by forming connections with healthy neurons and hijacking the electrical signals they produce
The new studies appear to confirm this, and even show how.
Monje's team found that some cancer cells were forming synapses — the connections between neurons — that could be seen with an electron microscope. They also found evidence of a more primitive direct connection between cancer cells and healthy brain cells.
Tumor cells "are integrating into neural circuits in the brain," Monje says, then using these connections to affect the behavior of neurons. "The cancer cells themselves are promoting the neuronal activity that then feeds back to drive the growth of the cancer."
Winkler and his team found virtually the same thing with a different set of glioma cells. "There's a massive amount of networking going on," he says.
A third study, led by researchers in Switzerland, found that when breast cancer cells move to the brain, they also can form connections with neurons.
And that raises several big questions, says Douglas Hanahan, an author of the breast cancer study and a scientist at the Swiss Institute for Experimental Cancer Research.
For example: when cancers from other organs spread to the brain, do they also connect to neurons? And what about cancers that spread to the peripheral nervous system, which extends beyond the brain and spinal cord?
Finally, Hanahan asks: "How might this neuronal signaling circuit in cancer cells be disrupted therapeutically, while sparing the adjacent normal neurons?"
The research is likely to have a seismic impact on brain cancer research, says Andres Barria, a neuroscientist at the University of Washington who studies synapses and wrote an editorial accompanying the three studies.
"My reaction was, wow," he says. "To show that [a tumor cell] actually makes real connections just like normal neurons will do is very amazing."
And that discovery could lead to new and better treatments for high-grade gliomas, which now typically kill a patient within two years.
"Our hope is that by decreasing the electrical signals that the tumors are receiving from the normal brain, that we might be able to complement existing therapies and extend survival and improve quality of life," Monje says.
Her team showed that an anti-epilepsy drug called perampanel reduced the growth rate of one type of glioma by 50% in mice.
But Barria advises caution when it comes to drugs that affect the connections between brain cells.
"Synapses are everywhere in the brain," he says. "So to target only the synapses between cancer cells and neurons, that's what's going to be tricky."
ARI SHAPIRO, HOST:
New research is helping us understand why certain brain cancers are so deadly. Three studies published today in the journal Nature show that these cancers can hijack the brain's own wiring in order to grow faster. NPR's Jon Hamilton reports that the discovery could lead to better ways to treat patients who have these tumors.
JON HAMILTON, BYLINE: The deadliest brain cancers are called high-grade gliomas, and they include the tumor that killed Senator John McCain in 2018. Dr. Michelle Monje of Stanford University has spent most of her career looking for a way to beat these tumors.
MICHELLE MONJE: High-grade gliomas are really an intractable set of diseases, and we've made very little progress clinically in effectively treating these terrible brain cancers.
HAMILTON: Five years ago, Monje was part of a team that found something really surprising. High-grade gliomas grew faster when the brain cells around them became more active. Monje's team suspected that was because active neurons produce a substance that serves as fuel for a glioma. So in 2017, the team took human glioma tumors and put them in the brains of special mice that had been genetically altered so they couldn't produce this fuel.
MONJE: There wasn't just a slowing in the tumor growth; there was a complete stagnation.
HAMILTON: Monje's research suggested that high-grade gliomas somehow cause healthy neurons to become more active and produce more fuel for the cancer. The new studies support that idea and suggest how the process works. Monje says it begins when glioma cells form synapses and other connections with healthy neurons.
MONJE: The cancer cells are integrating into neural circuits in the brain.
HAMILTON: Then, Monje says, the glioma cells use these electrical connections to make healthy cells become more active.
MONJE: The cancer cells themselves are promoting the neuronal activity that then feeds back to drive the growth of the cancer.
HAMILTON: The finding by Monje's group was confirmed by a second study led by scientists at the University of Heidelberg in Germany. A third study, led by researchers in Switzerland, found that when breast cancer cells move to the brain, they also can form connections with neurons. Monje says the challenge now is to figure out how to use this knowledge to help patients.
MONJE: Our hope is that by decreasing the electrical signals that the tumors are receiving from the normal brain that we might be able to complement existing therapies and extend survival and improve quality of life.
HAMILTON: Monje's lab has already shown the strategy might work. A drug used to treat epilepsy was able to interrupt those signals and slow tumor growth by 50% in mice.
Andres Barria of the University of Washington says the new studies are likely to have a seismic effect on brain cancer research.
ANDRES BARRIA: My reaction was, wow.
HAMILTON: Barria, who studies synapses, wrote a perspective piece that accompanies the new research. He says it's mind-boggling to think that cancer cells can create a synapse.
BARRIA: There was evidence before that excitatory activity in the brain could help these cells, but to show that it actually makes real connections just like two normal neurons will do is really amazing.
HAMILTON: Barria agrees with Monje that the discovery could lead to new and better drugs for high-grade gliomas. One approach, he says, would be to give a drug that prevents cancer cells from forming synapses with healthy cells.
BARRIA: The tricky part is that synapses are everywhere in the brain, so to target only the synapses between cancer cells and neurons, that's what is going to be tricky.
HAMILTON: But not impossible, he says, now that scientists have a better understanding of how these cancers work.
Jon Hamilton, NPR News.
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