January 14, 2021, by Nadia Jaber
Stress hormones can alter the behavior of some neutrophils, potentially causing dormant cancer cells to reawaken, a study suggests.
Credit: Medical Gallery of Blausen 2014. WikiJournal of Medicine. doi:10.15347/wjm/2014.010. CC BY-SA 4.0
For many cancer survivors, their worst nightmare is finding out that their cancer has come back. Even years after a seemingly successful treatment, cancer can start growing again, and scientists don’t know how this happens.
Now, a new study suggests that stress hormones may wake up dormant cancer cells that remain in the body after treatment. In experiments in mice, a stress hormone triggered a chain reaction in immune cells that prompted dormant cancer cells to wake up and form tumors again.
But if you are stressed, that doesn’t mean your cancer is going to come back, said the study’s lead researcher, Michela Perego, Ph.D., of The Wistar Institute Cancer Center. Several intermediate steps need to occur, Dr. Perego said, at least according to their studies in mice.
“There could be many different ways to wake dormant cells. We’ve shown one mechanism, but I’m very confident this is not the only one,” she added. The results of the new study were published December 2 in Science Translational Medicine.
While plenty of research has shown that stress can cause cancer to grow and spread in mice, studies haven’t shown a clear link between stress and cancer outcomes in people. But it’s difficult to study stress in people for several reasons, including challenges with defining and measuring stress.
Nevertheless, there could be many far-reaching effects of the new study findings, particularly in the realm of identifying new therapeutic leads, said Jeffrey Hildesheim, Ph.D., of NCI’s Division of Cancer Biology, who was not involved in the research.
“This study is like a gateway that will likely open up numerous other research directions into the effects of cancer therapies and stress on dormant tumor cells,” Dr. Hildesheim said. It could also spark research into the effects of nerves and the nervous system on tumor growth, he said.
Immune Cells Wake Up Dormant Cancer Cells
Some cancer treatments can push surviving cancer cells into hibernation. These dormant cells either stop growing or grow very slowly. Because there are so few of them, they’re impossible to find with standard tests, Dr. Perego explained. And they don’t usually cause any issues—unless they start growing again.
“We don’t know exactly what triggers them to come back. Why in that moment?” she said.
Dr. Perego studies how certain immune cells help cancer grow and spread. So, she wondered, could immune cells wake up dormant cancer cells?
To find out, her team created dormant cancer cells in the laboratory by genetically engineering lung cancer cells, or by treating lung, ovarian, and breast cancer cells with a common chemotherapy drug. Both kinds of dormant cancer cells survived but didn’t grow.
In lab dishes, dormant cells didn’t grow when mixed with B cells or T cells, two kinds of immune cells. But they started growing again when mixed with so-called “pro-tumor” neutrophils.
Neutrophils, a kind of white blood cell, are part of the body’s first line of defense against infections. But tumors can turn neutrophils into bad actors, coaxing them into helping the tumor grow and spread.
When the researchers transplanted dormant lung cancer cells into mice that lacked an immune system, these cells didn’t form tumors. But if the dormant cancer cells were transplanted along with pro-tumor neutrophils, most of the mice developed lung tumors.
Stress Hormones Alter Neutrophils
With that finding, Dr. Perego and her colleagues faced a key question: What turns neutrophils rogue if there are no tumors left in a patient’s body? Because some studies have linked chronic stress to cancer progression, the scientists explored the effects of stress on neutrophils.
Stress hormones like adrenaline and norepinephrine set off a chain reaction involving neutrophils and dormant cancer cells, the researchers found. In lab dishes, stress hormones caused neutrophils to spit out a protein duo known as S100A8/A9. These proteins made neutrophils produce certain lipids that, in turn, awakened dormant lung cancer cells.
A mixture of norepinephrine and neutrophils also woke up human cancer cells made dormant from chemotherapy.
What’s happening is “a type of cascade,” Dr. Perego said. “One component of this cascade alone doesn’t work. Neutrophils alone, S100A8/A9 alone, and stress hormones alone don’t work” to wake up dormant cells, she explained. “But when you have this chain of events…it reawakens dormant cells.”
Preventing Recurrences in Stressed Out Mice
The researchers next explored whether the same cascade occurred in mice that were stressed from being confined for a few hours a day.
Stressed mice had more neutrophils in their lungs and spleens than unstressed mice, the scientists found. The stressed mice also had more S100 proteins in their blood. Dormant lung cancer cells formed tumors in stressed mice but not in unstressed mice.
However, when stressed mice were treated with a beta blocker, a blood pressure medicine that blocks stress hormones, dormant cancer cells couldn’t form tumors. The researchers saw similar effects when mice were treated with tasquinimod, a drug that blocks the activity of S100 proteins and has been tested in people with prostate cancer.
The team also looked at blood samples from 80 people who had had surgery to remove their lung tumors. For 17 patients, the cancer came back (recurred) within 3 years of their surgery. For the others, the cancer came back more than 3 years later or didn’t come back at all.
Earlier recurrence was more likely among patients with high levels of S100 proteins or norepinephrine in their blood than among those with low levels. Similarly, a 2019 study linked levels of S100 proteins in melanoma tumors with cancer metastasis and how long patients lived. However, a recent analysis of several studies found that the use of beta blockers wasn’t linked with longer survival of cancer patients.
Opening the Floodgates for Research
Researchers have suspected that there might be a link between stress and cancer for some time. But “the mechanism behind that link remains somewhat elusive,” Dr. Hildesheim said. This study “makes a significant contribution” by identifying various components that might, in part, underlie that connection, he noted.
What’s more, this same mechanism could be contributing to cancer growth and treatment resistance in other ways, Dr. Hildesheim said. “The nervous system could be impacting [cancer] from multiple angles,” he added.
A 2019 study, for example, showed that stress hormones can increase the number of pro-tumor immune cells in tumors. That could mean that stress not only wakes up dormant tumor cells but also provides the right environment for them to grow, Dr. Hildesheim explained.
“It’s the worst of both worlds,” he said.
But, like Dr. Perego, he thinks it’s something that could be addressed by combining treatment approaches. Scientists are working to develop drugs that block the activity of or kill certain kinds of dormant cells called senescent cells. Finding ways to target senescent and dormant cells are two focuses of a recent partnership between NCI and Cancer Research UK.
Chemotherapy, radiation, and targeted therapy can all turn cancer cells into senescent cells. When combined with these traditional treatments, it’s possible that drugs that target senescent cells may prevent cancer from coming back, Dr. Hildesheim said.
Stress is a part of life. You feel it when you’re preparing for the holidays, stuck in traffic or worrying about a friend’s health. While a little stress is nothing to fret about, the kind of intense worry that lingers for weeks or months may make it hard for you to stay healthy.
“Stress has a profound impact on how your body’s systems function,” says Lorenzo Cohen, Ph.D., professor of General Oncology and Behavioral Science, and director of the Integrative Medicine Program at MD Anderson. Health experts are still sorting out whether stress actually causes cancer. Yet there’s little doubt that it promotes the growth and spread of some forms of the disease. Put simply, “stress makes your body more hospitable to cancer,” Cohen says.
Not all stress is equally harmful
There are two different types of stress, and only one seems to be really bad for your health, says Anil K. Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine at MD Anderson.
Short-term or acute stress, like the type you might feel before giving a speech or fighting holiday shopping crowds, tends to subside as soon as the event passes. “It’s stress that comes from situations you know you can manage or will be over at some set time,” Cohen says.
But long-term or chronic stress is more damaging. That type of stress springs from situations that last many weeks or months with no definite end point. “Caring for a sick loved one or dealing with a long stint of unemployment are common causes of chronic stress,” Cohen says.
This type of no-end-in-sight stress can weaken your immune system, leaving you prone to diseases like cancer. It also ups your risk for digestive problems and depression. “Chronic stress also can help cancer grow and spread in a number of ways,” Sood says.
Stress hormones can inhibit a process called anoikis, which kills diseased cells and prevents them from spreading, Sood says. Chronic stress also increases the production of certain growth factors that increase your blood supply. This can speed the development of cancerous tumors, he adds.
Find healthy ways to manage stress
What can you do about stress? Removing the cause is the clear answer. But that’s not always possible when it comes to the types of things that cause chronic stress, Cohen says.
Even if you can’t rid yourself of the source of your stress, you can learn to manage it. This can help you keep a lid on chronic stress. It also can help you prevent minor sources of stress from lingering to a point where they’re affecting your health. Below, Cohen shares stress-reducing strategies.
Talk to a professional
A psychiatrist or psychologist can teach you healthy ways to manage your stress.
Strategies may include talk therapy and cognitive behavioral therapy (CBT). These can help your brain uncover the connections between your thoughts, emotions and behaviors. “CBT can provide you with mental tools to manage the types of worry and anxiety that screw up your immune system and increase your disease risks,” Cohen says.
Practice meditation or yoga
Mindfulness meditation and yoga have been proven to combat stress. These movement-based activities give your mind a break from stress. They also can improve your mood and quality of life.
Aim for at least two 20-minute periods a day of meditation or similar relaxation techniques, Cohen says. That time shouldn’t include stimulating activities like watching television. “Sit quietly and try to keep your mind off any concerns. Think about visiting your favorite vacation spot or a quiet, safe place like your garden.”
Mediation and yoga also can help your brain soften the links between your thoughts, your emotions and unhealthy biological changes, he says. Put simply, these practices dampen your brain and body’s reactions to stressful events.
Get adequate sleep
“Getting eight hours of sleep each night is a great defense against stress,” Cohen says. Why? A full night of sleep is essential to proper immune function. It also affects your mood, memory and ability to focus, experts say. Sticking to a regular sleep schedule, avoiding TV in bed and exercising regularly can all help you sleep more soundly.
Take stress seriously
It’s important to understand the negative consequences of stress, especially when it comes to your cancer risks. “Chronic stress is not something anyone in our society should take lightly,” Cohen says.
If you feel crankier than usual, you don’t have the energy you once had or you’re sleeping poorly, all of those could be signs of stress, Cohen says. Take steps to fix your problem before it affects your health in more serious ways.
Request an appointment at MD Anderson’s Lyda Hill Cancer Prevention Center online or call 877-632-6789.
