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How the body’s nerves become accomplices in the spread of cancer

In 1998, Gustavo Ayala, a young pathologist, landed at Baylor College of Medicine in Houston, Texas, ready to start to see patients. But his state medical license was delayed, and during 4 months of unexpected freedom, he found himself hunched over lab dishes, absorbed by a strange kind of cellular courtship.

Ayala hadn't planned to do research full time, but a little-explored feature of cancer enticed him: the tendency of some cancer cells to wrap around nerves and grow along them. He had seen that "perineural invasion" in cancer patients and knew it often signaled an aggressive tumor and a poor prognosis. "But nobody knew how it happened," Ayala says. "There was no biology."

So Ayala put spinal nerves from a mouse in a dish next to human prostate cancer cells. What he saw was a symbiotic dance: Before the cancer colony invaded the nerves, the nerves reached out to the cancer. They elongated toward the cancer cells and grew into the colony's midst. In turn, the cancer cell colony ballooned. The attraction, it seemed, was mutual.

Since that observation, Ayala's group and others have discovered that the peripheral nerves that branch through our bodies and regulate our organs are crucial partners to cancer as it grows and spreads. Those nerves churn out molecules that appear to aid the growth of cancer cells, and they alter surrounding tissue in ways that can make it more hospitable to cancer. "They're not a bystander," says Paola Vermeer, a cancer biologist at Sanford Research in Sioux Falls, South Dakota, who studies cancer-nerve interaction. "They're an active participant in the disease process."

To some experts, those revelations from basic biology help explain a controversial link between chronic stress and cancer progression. The work has also prompted several clinical trials testing whether blocking nerve signaling slows tumors' spread. Those studies have yet to show long-term benefits for patients, but optimism is high. "The field, I feel, is about to explode," Vermeer says. "People are starting to take notice."

A dangerous partnership

Recent studies have revealed many lines of communication between tumors, nerves, and other nearby cells. Their elaborate crosstalk seems to promote the growth and spread of cancer, in part through the release of stress-related hormones.

Sympathetic nerves branching through the body release the hormone norepinephrine into nearby tissue. When it hits receptors on cancer cells, it can set off a signaling pathway that prompts growth. Green light for growth Norepinephrine released by nerves activates receptors on the endothelial cells that make up blood vessels. That signal prompts the formation of new blood vessels that can bring much-needed oxygen into a growing tumor. New blood Nerves can prompt certain immune cells to stand down. Some of their signals seem to nudgemacrophages into a mode that promotes cancer growth.They may also prevent T cells from attacking cancer cells directly. Extra protection Cancer cells release neurotrophicfactors—molecules that encourage nerves to branch and elongate toward the tumor. Luring nerves Norepinephrine Macrophage Neurotrophicfactor Tumor cells Nerve cell Blood vessel Tumor

It's not outlandish to think the nervous system could become complicit in cancer's growth and spread. Cancer is adept at exploiting the body's normal functions—for example, by stimulating the growth of new blood vessels that nourish the invading cells. The disease manages to "curate the best of the body and use it to promote its survival advantage," says Paige Green, head of the National Cancer Institute's research program on basic biobehavioral and psychological sciences in Bethesda, Maryland. By studying how cancer "curates" protective mechanisms in the immune system, scientists have developed powerful drugs to thwart those mechanisms, sparking a multibillion-dollar industry.

The role of nerves has taken longer to emerge, says cancer neurobiologist Hubert Hondermarck of the University of Newcastle in Australia. Before the development of precise ways to label neurons, the small nerve branches in and around tumors were easy to overlook. And even after those tools were available, "There was no particular interest in studying nerves in depth among the cancer community," Hondermarck says.

Many cancer labs were absorbed in studying genetic mutations in cancer cells themselves, not the body's cancer-promoting signals, Ayala says. In the early 2000s, his focus on cancer-nerve crosstalk made him an outsider. "I was called the nerve guy."

But Ayala wasn't truly alone. Others were studying nerves in hopes of pinning down an elusive connection between cancer and stress. One such researcher was Anil Sood, a cancer biologist at the University of Texas MD Anderson Cancer Center in Houston. He was intrigued by findings that tumors grew bigger and faster in lab animals that were stressed—for example, by being physically restrained or socially isolated. Some studies had even suggested chronic stress in people made cancer more likely to progress. But how those proposed links worked wasn't clear, he says. Among researchers interested in stress and cancer, "There was a feeling that hardcore scientists would view these kinds of observations to be ‘soft science.’"

So Sood and others went hunting for mechanisms. The researchers focused on the sympathetic nervous system, which orchestrates our "fight or flight" response to a perceived threat. The hormones epinephrine and norepinephrine play a key role in the response, increasing heart rate and blood pressure. Sympathetic nerves, which weave through our organs and signal to them, release those hormones into nearby tissue. (The adrenal glands perched on our kidneys secrete the same hormones into the bloodstream, which distributes them widely.)

Many cells in the body, including many cancer cells, are studded with β-adrenergic receptors, to which epinephrine and norepinephrine bind. And activating those receptors on cancer cells seems to encourage them to grow. In 2006, Sood's team reported it could prompt a mouse's ovarian tumor to grow larger by either exposing mice to chronic stress or giving the animal a drug that activates β-adrenergic receptors. Both interventions prompted cancer cells to recruit and nourish nearby blood vessels that, in turn, fueled their growth. Blocking the receptors prevented this growth.

That study and others showed cancer cells were alert to signals from the nervous system. Then, in 2013, research oncologist Claire Magnon and colleagues in the lab of cell biologist Paul Frenette at Albert Einstein College of Medicine in New York City went further. The researchers revealed that the small nerve fibers near a tumor were, at least sometimes, essential to the tumor's growth. The team grafted human prostate tumors into mice and then either sliced out the surrounding nerves or destroyed them with a toxic chemical. Without neighboring nerves, the tumor failed to grow. In people, the team found that the higher the density of nerves in and around a prostate tumor, the faster the tumor tended to spread outside the prostate and the faster the cancer tended to recur after surgery. Studies by other groups showed that removing nerves could also prevent gastric and pancreatic tumors from forming. And at many other sites—including the breast, colon, and lung—researchers correlated nerve density with more aggressive disease.

Gustavo Ayala has probed basic interactions between nerves and tumor cells that could lead to new therapies.


They also began to document the ways that cancer and nerves cozy up. Nerves entwined in blood vessels can hitch a ride into a tumor as it recruits blood vessels to supply it with oxygen. Cancer cells also produce molecular signals that can prompt nearby nerves to form new projections snaking into and around the tumor. Some evidence suggests signals from cancer can even prompt the body to make brand-new neurons from stem cells.

A provocative paper published in Nature this year showed that, in mice, neural precursor cells in the brain appear to migrate to a prostate tumor to supply it with neurons. The study, by Magnon, who is now at the French biomedical research agency INSERM in Paris, and collaborators, pointed to an unexplored path of communication between cancer and the central nervous system.

Why would cancer cells form alliances with nerves in the first place, tuning in to their signals and drawing them close? One idea is that a nerve-rich neighborhood is simply a friendly place for cancer, says Steven Cole, a genomics researcher at the University of California, Los Angeles. Because nerves expand and migrate regularly, they crank out molecules that encourage growth and motility—which a nearby cancer cell will gladly drink up. Cole's group also found that signals from sympathetic nerves nudge immune cells called macrophages to deconstruct nearby tissue, secrete growth-promoting molecules, and recruit blood vessels. "The cancer cells love it," he says.

Another idea is that listening to signals from sympathetic nerves helps cancer cells synchronize their invasion to periods of high stress, says neuroimmunologist Shamgar Ben-Eliyahu of Tel Aviv University in Israel. As cancer grows, it risks provoking T cells trained to attack and kill the body's wayward cells, he explains. But when the body is on high alert and sympathetic nerves are most active, the immune system is tamped down. "If the tumor is smart enough to expose its cells to the immune system only when the immune system is suppressed, then it's an advantage."

Some researchers view evidence about the role of nerves as a long-awaited mechanistic link between stress and cancer. "The idea that tumors can be so controlled by these nerves—all of a sudden it really brings some clarity into why various types of stress can be so bad for people," says Elizabeth Repasky, a cancer researcher at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Cole notes that when he and others talk of a cancer-promoting stress response, they don't mean the psychological experience commonly referred to as stress. That fretful, frazzled mental state doesn't align perfectly with the release of stress hormones into our tissues and veins, he says. Still, he and others believe a state of chronic threat or insecurity—when a person doesn't know how to meet basic needs such as food, shelter, and companionship—can manifest in a physical reaction that may drive cancer.

"I see these patients … who are taking care of their small children, maybe their parents, are living on aid or assistance, and now have some malignancy," says Jennifer Knight, a psychiatrist specializing in cancer at the Medical College of Wisconsin in Milwaukee. "They're in a chronic fight-or-flight mode because they're under heightened threat, not getting basic needs met." Knight is investigating whether stress-induced nerve activity could help explain why people of lower socioeconomic status do worse after a cancer diagnosis, even after factors such as access to care are controlled for.

"There are still a lot of unknowns" about the stress-cancer link, Sood says. Nerve activity may promote cancer regardless of whether a person is under particular stress, he says, and nerves may be a driver only at particular stages in a tumor's evolution.

A fundamental problem, Hondermarck adds, is that objectively measuring the intensity of stress or defining what kind of stressful experience is relevant to disease is hard. "The potential relationship between stress and cancer has been in the air for a long time," he says, "but has never been really demonstrated."

Regardless of the role of stress in cancer, targeting the nervous system with drugs might help treat the disease. Knight, Repasky, Frenette, and Sood are all investigating a common class of drugs called β blockers. Used since the 1960s to reduce blood pressure and treat cardiovascular disease, and sometimes prescribed to manage short-term anxiety, they block β-adrenergic receptors to keep heart rate low.

Some retrospective studies have reported that people who happened to be diagnosed and treated for cancer while taking β blockers had better prognoses than patients not taking the drugs. But other studies found no benefit. So, several groups have launched prospective trials to test β blockers more systematically. Ben-Eliyahu has focused on the drugs' potential to prevent metastasis after surgery, when residual disease often lingers around the surgical site or in distant parts of the body. He wondered whether administering a β blocker alongside another drug to reduce the cancer-promoting inflammatory reaction to surgery could make any leftover cancer less likely to spread.

In 2017, his team published results from a clinical trial, conducted with Cole and other collaborators, that enrolled 38 women with breast cancer who were slated for surgery. Five days before the procedure, half started to take the β blocker propranolol and the anti-inflammatory drug etodolac. The study had too few participants to draw conclusions about survival or disease recurrence. But breast tumors from women getting the drug cocktail expressed fewer genes associated with metastasis than tumors of women taking placebo. Ben-Eliyahu says his group now has similar, unpublished results from 34 people with colorectal cancer.

The field, I feel, is about to explode. People are starting to take notice.

Paola Vermeer, Sanford Research

Larger trials are in the works. Ben-Eliyahu and colleagues have launched a trial at Israeli medical centers that aims to recruit 210 people with pancreatic cancer, some of whom will start to take propranolol and etodolac a few days before surgery to remove their tumors. The researchers plan to track survival over 5 years.

But the team is having trouble raising money for the trial, Ben-Eliyahu says. Other groups are struggling, too. "Those trials are really challenging for reasons that are incredibly annoying when you actually think about them," Cole says: Industry sponsors don't see a way to profit from drugs that long ago lost patent protection. "It's hard to even recruit patients because their docs are all putting them on studies of these fabulously remunerative brand-new therapies, as opposed to this β blocker that my grandfather took when he had a heart attack or something," he says.

β blockers aren't the only option for targeting the nervous system's role in cancer. Future studies might also explore the potential of antibodies that bind to and disable proteins released by cancers that promote nerve growth, Hondermarck says. And Cygnal Therapeutics, based in Cambridge, Massachusetts, is pursuing cancer treatments that target the interaction between cancer and nerves, though it has yet to share details of its strategy.

Two decades after his first curiosity project, Ayala—now at McGovern Medical School at the University of Texas Health Science Center in Houston—is still studying the cancer-nerve relationship and has begun to pursue possible therapies. Last year, his team reported in The Prostate that in four men with prostate tumors, injecting the nerve toxin botulinum into one side of the tumor prompted more cancer cells to die there than on the untreated side. He's preparing to test the approach in a larger group of men.

Ayala is energized by the new enthusiasm for the field. That he has had to spend some time in the academic wilderness is "absolutely normal," he says. But in his view, studies focused on sympathetic nerves barely scratch the surface of cancer-nerve interactions. Some research has suggested a role for parasympathetic nerves, which counteract sympathetic signals to return the body to rest, and for sensory nerves, which relay various stimuli to the brain. Ayala is preparing to publish a study on the influence of two more nerve types, defined by the proteins they express. He expects that dozens of distinct nerve types form complex—and consequential—partnerships with cancer.

"This is a story to be written by many people over the next 30 years," he says. "There's much more out there."

*Update, 13 September, 11:05 a.m.: This story was updated to mention Claire Magnon’s role in the 2013 study.