Why do sleeping cancer cells awaken?

Dormant cancer cells
When cancer recurs in patients who were told after treatment they have no evidence of disease, it’s often because dormant, cancer cells have been awakened.

It’s been said that when all’s well, it’s best to let sleeping dogs lie. In other words, don’t instigate trouble or invite the unpredictable. When it comes to cancer, that may not always be possible.

When cancer recurs in patients who have received care and were told they have no evidence of disease, it’s often because sleeping, or dormant, cancer cells left behind after treatment have been awakened. How or why these previously undetected cells were aroused is usually a mystery, as is why cancer may return in one patient but not another with the same or a similar diagnosis. But, like those recently awakened dogs, they are likely to disturb the status quo and create new challenges.

“You can never truly know, when you have two people with similar cancers, why one person has a recurrence but the other doesn’t,” says Stephen Lynch, MD, Vice Chief of Staff at Cancer Treatment Centers of America® (CTCA), Phoenix. “A lot of it is that there’s a microenvironment that we can’t account for.”

In recent years, however, researchers have made progress in better understanding the behavior of slumbering cancer cells, where they may hide and why they may reactivate. Research into ER-positive breast cancer, for instance, has led to new recommendations on hormone treatments that may reduce the risk of recurrence and lead to better outcomes. New research is also shedding new light on the impact of stress, inflammation and other conditions that may promote cancer recurrence.

Dormant, yet difficult

The presence of dormant cells in previously treated patients and the conditions that allow them to awaken are among the most vexing issues for cancer doctors and researchers, for a number of reasons, including:

  • Some cancer cells are able to embed themselves and hide in bone or organs, evading detection and treatment for years before reawakening.
  • Because they’re dormant, they may be able to avoid chemotherapy drugs designed to kill fast-growing cells.
  • Dormant cancer cells may exist in such small numbers that they cannot be detected.

“We have to have to understand the limitations of scans,” Dr. Lynch says. “They can’t always detect microscopic disease.”

Dormant cells often are those that have broken away from the primary tumor and traveled to distant parts of the body. When they awaken, they create metastatic tumors that may be more difficult to treat than the original cancer. In an analysis published in April 2020 in the Experimental & Molecular Medicine’s journal, researchers at South Korea’s Gwangju Institute of Science and Technology describe awakened cancer cells as “the final step of the metastatic outbreak.” Metastasis accounts for 90 percent of all cancer deaths.

“The existence of [dormant cancer cells (DCCs)] has led to the emergence of therapy resistance, and most importantly, the cells may resume growth, raising the risk of lethal metastatic outbreaks even after a long latency period of months to years,” the researchers wrote. “For these reasons, DCCs have been attracting significant interest as a therapeutic target for improving clinical outcomes.”

The challenges of finding and treating slumbering cancer cells is why some doctors choose their words carefully, even when a patient’s treatment appears to have gone well.

“We don’t want to add any stress when we talk to patients, but we usually try to avoid absolutes,” Dr. Lynch says. “I like to talk about where they are in their journey, and if they’re at that point where there is no evidence of disease, I tell them, “You’re exactly where we want you to be after treatment.’”

Hide and seek

It’s hard to learn about something you can’t see, or even find. That’s one of the challenges of dormant cancer cells. To learn why they may reawaken, scientists are trying to determine why they went dormant in the first place.

The difficulty is finding cancer cells that don’t want to be found. Using new technology in mice, researchers at the Garvan Institute of Medical Research in Australia were able to find multiple myeloma cells hidden in bone, a common place for cancer metastases. “Once a cancer spreads to bone, it becomes notoriously difficult to treat,” researcher Peter Croucher said in a Garvan news release. “We want to change that. The first step to new treatment approaches is to understand exactly what’s happening to those cells.”

The Australian researchers not only identified genes that may determine a cell’s sleep cycle, but also external forces from surrounding cells that may help either keep cells asleep or reactivate them. “Now that we have an understanding of the forces that act on sleeping cancer cells in the skeleton, we’re working to understand more about what goes on inside those cells when they’re sleeping, and as they begin to wake,” Croucher said.

Creating a conundrum

If doctors can develop tools to help find and identify dormant cancer cells while they’re sleeping, taking the next step may create new challenges and questions. Researchers are faced with several options on how to deal with the sleeping cells:

  • Do they keep the cells dormant and develop strategies to keep them asleep?
  • Do they try to kill the cells while they sleep? This may be difficult since their dormancy has allowed them to resist treatment.
  • Do they reactivate the cells so they’re more susceptible to drug treatments, such as chemotherapy?

“The danger of waking them up is that if your drug doesn’t work or you don’t eradicate all of them when you’ve woken them up, the patient is going to develop recurrent disease more rapidly,” Simon Buczacki, MD, told Cancer Research UK.

Doctors at the Fred Hutchinson Cancer Research Center in Seattle are looking into combining chemotherapy with antibodies that target integrins, which are endothelial cells that sometimes help protect sleeping cells hidden in bone. Early research shows that this combination may help prevent bone metastases from forming.

“This is the first study to show that disseminated tumor cells, when they’re quiescent, can be sensitized to chemotherapy,” Fred Hutchinson researcher Cyrus Ghajar, PhD, was quoted as saying in the National Cancer Institute’s Cancer Currents blog.

Wake-up call

To better understand why dormant cells awaken, researchers have turned to some known cancer risk factors—particularly stress and inflammation, which often go hand-in-hand.

While the direct connection between stress and cancer is still being explored, researchers say chronic stress may create conditions in the body that promote tumor growth. Stress releases hormones that help heighten specific senses during difficult times. But chronic stress over time may increase growth factors that promote cancer cell growth. Stress may also stop the body from killing off diseased or damaged cells, a process called anoikis.

In December 2020, a group of researchers tied stress factors to the reawakening of lung cancer and ovarian cancer cells in previously treated patients. Their research found that stress hormones may lead to the production of proteins that promote inflammation, which led to the reactivation of cancer cells and the growth of new tumors in mice.

“Our data suggest that stress hormone levels should be monitored in patients recovering from cancer and that managing stress to keep those hormones at bay would be beneficial to prolong remission,” The Wistar Institute researcher Michela Perego, PhD, said in a National Institutes of Health article.

Scientists at Cold Spring Harbor Laboratory in New York also are analyzing inflammation’s role in cancer cell reactivation. Their research indicates that inflammation in the lungs may cause dormant cancer cells in the lungs, breast or prostate to start regrowing. Exposure to tobacco smoke is a leading cause of lung inflammation.

Lifestyle choices

Many cancer survivors recognize that their cancer could return. And while they may have little control over the microscopic factors that help hidden cells awaken, they can take control of lifestyle choices to help reduce their risk of a cancer recurrence, including:

  • Losing weight
  • Quitting all tobacco use
  • Eating a healthy diet
  • Exercising
  • Moderating or quitting alcohol consumption
  • Getting restful sleep
  • Reducing stress

Learn about steps you can take if your cancer returns.