Stress Shown To Awaken Sleeping Tumor Cells in Mice

Stress hormones and white blood cells called neutrophils may raise the risk of tumors returning years after treatment by awakening dormant cancer cells in the body, suggests a study of mice and data from 80 patients with lung cancer. The new research was published in the December 2 issue of Science Translational Medicine.

The experiments help answer the enduring question of why cancers can return months or years after being treated with chemotherapy or surgery. The recurrence of tumors is a major cause of overall deaths from cancer in patients, so understanding why and how it happens is a critical goal for cancer researchers.

The scientists found that stress hormones caused neutrophils to release proteins that awakened dormant cancer cells in mice. These same proteins were also linked to a higher risk of relapse in patients with lung cancer who had undergone surgical removal of their tumors.

"Thus, we think that monitoring levels of stress hormones in patients undergoing cancer therapy might be very important," said Michela Perego, a research assistant professor at The Wistar Institute at the University of Pennsylvania and lead author of the new study.

Rates of relapse and recurrence depend on the type of cancer, but recurrence has been described as the rule, rather than the exception for aggressive malignancies such as small-cell lung cancer.

The recurrence of tumors can even occur in patients who had successful surgeries that seemingly removed entire tumors. One study of 42 patients with invasive lung cancer in the spine showed that even after having the entire tumor surgically removed, only 24 of the patients remained free of recurrence after a median of 26 months.

HOW TUMOR CELLS REAWAKEN

It's still unclear exactly what biological mechanisms prompt tumors to recur, but researchers suggest that recurrence may unfold as tumor cells that remained hidden throughout treatment begin to reawaken. These are "sleeping" tumor cells that spread in the body and then entered a dormant state while the cancer was initially active.

"We know that cancer can come back because some cells that were spared by the initial treatment can stay hidden in our body," said Perego. "Unfortunately, little is known about how and when these cells reawaken from dormancy and give rise again to cancer."

Perego and her team began by examining the connections between dormant tumor cells and other cells in the body. They focused much of their attention on myeloid-derived suppressor cells, a type of neutrophil that suppresses the immune system and has been linked with the progression of tumors and poorer clinical outcomes.

The team analyzed lung cancer cells from genetically modified mice and then isolated the cells and forced them into a dormant state. While studying the cells in the lab, the researchers discovered that hormones such as norepinephrine and cortisol — which control how the body responds to stressful situations — reactivated the dormant cancer cells and caused them to spread.

Turning back to mice, the scientists found that exposing the animals to stressful situations raised levels of stress hormones, which caused neutrophils to release molecules called S100A8/A9 proteins. These proteins then prodded the neutrophils to accumulate and release fatty molecules called lipids, which in turn prompted lung cancer cells to reawaken from dormancy.

EXPLORING HOW TO KEEP CANCER CELLS ASLEEP

The team repeated these stress experiments but gave the mice an experimental beta-blocker that blocks the effects of stress hormones. This compound prevented neutrophils from secreting the proteins, and the treated animals had better survival rates than the untreated, stressed-out mice.

The scientists also studied blood samples from 80 patients who had their lung cancers removed with surgery. The patients who harbored higher levels of S100A8/A9 proteins in their blood were more likely to have experienced recurrence 33 months after surgery, according to the study.

Based on the study's results, Perego speculates that controlling levels of stress hormones might achieve longer tumor-free survival times for cancer patients, especially if combined with standard therapies. But she stressed the need for further research before any firm conclusions can be drawn for human therapies.

The authors cautioned their results are limited by a lack of knowledge of the molecular mechanisms at play. Part of the issue is that there are currently no good models for studying the dormancy of tumors in mice, which limits how much scientists can learn about the effects of stress on cancer cells on the biological level.

However, Perego's team said that researchers could still take several routes to try to reduce the risk of tumors recurring, such as by giving patients beta-blockers to target stress responses. This approach has some support from previous studies, which have shown that beta-blockers can extend survival in patients with lung cancer and reduce the risk of recurrence in breast cancer.

Scientists could also attempt to directly target S100A8/A9 proteins with compounds such as tasquinimod, an experimental cancer therapeutic. Although tasquinimod did not show strong overall survival benefits in a phase 3 clinical trial, Perego and her colleagues said the compound, or similar treatments, might still be effective for delaying the progression of tumors that have not yet started to grow.

Reference: Perego M, Tyurin VA, Tyurina YY, et al. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Sci. Transl. Med. 2020;12(572). doi:10.1126/scitranslmed.abb5817

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