McKenzie Prillaman in Nature: Lightning bolts of lime green flashed chaotically across the computer screen, a sight that stunned cancer neuroscientist Humsa Venkatesh. It was late 2017, and she was watching a storm of electrical activity in cells from a human brain tumor called a glioma. Venkatesh was expecting a little background chatter between the cancerous brain cells, just as there is between healthy ones. But the conversations were continuous, and rapid-fire. “I could see these tumor cells just lighting up,” says Venkatesh, who was then a postdoctoral researcher at Stanford University School of Medicine in Stanford, California. “They were so clearly electrically active.”
She immediately began to think about the implications. Scientists just hadn’t considered that cancer cells — even those in the brain — could communicate with each other to this extent. Perhaps the tumor’s constant electrical communication was helping it to survive, or even to grow. “This is cancer that we’re working on — not neurons, not any other cell type.” To see the cells fizz with so much activity was “truly mind blowing,” says Venkatesh, who is now at Harvard Medical School in Boston, Massachusetts. Venkatesh’s work formed part of a 2019 paper in Nature1, which was published alongside another article2 that came to the same conclusion: gliomas are electrically active. The tumors can even wire themselves into neural circuits and receive stimulation directly from neurons, which helps them to grow.
The findings have been pivotal in the emerging field of cancer neuroscience, in which researchers are parsing the many ways in which cancer — even outside the brain — co-opts the nervous system for its own benefit. In much the same way as tumors recruit blood vessels to feed themselves and grow, cancer relies on the nervous system for everything from initiation to spread.
The interaction between oncology and neuroscience is just beginning to unravel in this once-overlooked part of the tumor’s environment. Scientists are starting to understand which neurons and signals are involved, but new-found interactions with the immune system are making the story even more complicated. As researchers dig deeper into the relationship between cancer and the nervous system, therapies that target the connections are emerging. Some of these treatments use existing drugs to improve outcomes in people with cancer.
“Where we’re headed with this is helping patients,” says cancer biologist Erica Sloan at Monash University in Melbourne, Australia. “Yes, there’s the intellectual delight of understanding what goes on at the biology level. But the key goal is, ‘How do we translate this?’”
Invasion and persuasion
Scientists first spotted liaisons between cancer cells and neurons almost 200 years ago. In the mid-nineteenth century, French anatomist and pathologist Jean Cruveilhier described a case in which breast cancer had invaded the cranial nerve responsible for facial movement and sensations.
This was the first account of perineural invasion, in which cancer cells weave in and around nerves — and then spread. The phenomenon is a sign of an aggressive tumor and foreshadows poor health outcomes.
For a long time, scientists and health professionals thought that nerves served passively as a highway to transport cancer and its associated pain. Many viewed the nervous system as “the victim — the structure that gets destroyed by or damaged by the cancer”, says neuro-oncologist Michelle Monje at Stanford University School of Medicine, who was Venkatesh’s adviser.
But in the late 1990s, urological pathologist Gustavo Ayala, now at the University of Texas Health Science Center at Houston, started investigating the interaction a little more closely. He placed mouse nerves in dishes speckled with human prostate cancer cells. Within 24 hours, the nerves began growing little branches called neurites, which reached out towards the diseased cells. Once they made contact, the cancer traveled along the nerves until it reached the neuronal cell bodies3.
Nerves weren’t just bystanders: they actively sought a connection with cancer. “I thought it was real, and I decided to make it my career,” says Ayala. He soon became known as ‘the nerve guy’. “People didn’t quite make fun, but they didn’t share my interest in the field,” he says.
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