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.
Emotional and social support can help patients learn to cope with stress. Such support can reduce levels of depression, anxiety, and disease- and treatment-related symptoms among patients. NCI’s page on Emotions and Cancer has tips for coping with the many emotions that arise with cancer.
There is some evidence that successful management of stress through social support is associated with better clinical outcomes for people with breast cancer (10). Social support has also been linked to lower levels of stress-related hormones that can promote tumor progression in ovarian cancer (10, 18).
Another approach to cope with stress is by being physically active. A report of the 2018 American College of Sports Medicine International Multidisciplinary Roundtable on Physical Activity and Cancer Prevention and Control found “sufficient” evidence to conclude that moderate-intensity physical activity during and after cancer treatment can reduce anxiety and depressive symptoms among cancer survivors (19). There is also evidence suggesting that physical activity is helpful in preventing depression among survivors of childhood cancer (20).
People who are experiencing significant stress with a cancer diagnosis may also want to consult their doctors about a referral to an appropriate mental health professional. In fact, some expert organizations recommend that all cancer patients be screened with an appropriate tool, such as with a distress scale or questionnaire, soon after diagnosis as well as during and after treatment (21, 22) to gauge whether they need help managing stress or are at risk for distress (23).
Treatment of significant distress, depression, and anxiety under the care of a mental health professional might include psychotherapy (talk therapy) and/or antidepressants or other medication. The choice of treatment should be personalized, ideally as a joint decision between the patient and the health care provider.
Researchers are studying novel psychotherapeutic approaches to lessen depressive symptoms such as distress and hopelessness in people with cancer. In one randomized clinical trial of people who had recently been diagnosed with advanced cancer, three to six sessions of a tailored psychotherapy intervention reduced symptoms of depression (24). Results from the trial also suggest that the approach may help prevent the onset of depression in those with advanced disease.
Another randomized clinical trial compared two different mindfulness-based cognitive therapy interventions—one delivered in person, the other electronically—with usual treatment in reducing psychological distress in people with cancer (25). Both interventions reduced elements of distress like fear of cancer recurrence and increased mental health–related quality of life, mindfulness skills, and positive mental health.
A resurgence of academic research into the therapeutic potential of psychedelic drugs has produced preliminary evidence for the possible role of psilocybin-assisted psychotherapy in the treatment of cancer-related anxiety, depression, and existential distress (26).
988 Suicide & Crisis Lifeline toll-free at 988 or 1-800-273-TALK (8255). You also can text the Crisis Text Line (HELLO to 741741) or use the Lifeline Chat on the 988 Suicide & Crisis Lifeline website.
If you are in immediate distress or are thinking about hurting yourself, call thetoll-free at 988 or 1-800-273-TALK (8255). You also can text the(HELLO to 741741) or use the Lifeline Chat on thewebsite.