"Sleeping" cancer cells in the lungs can be excited by COVID and influenza

Inflammation from respiratory infections seems to be the culprit, a study on mice showed.

In the lungs of some people who have survived breast cancer, tumor cells are hidden, which can remain inactive for decades - until one day they cause a relapse. Now experiments on mice show that these outcast cells can be excited from sleep by common respiratory diseases such as COVID-19 or flu.

The results published in Nature on July 30 seem to apply to humans as well: data from thousands of people show that SARS-CoV-2 coronavirus infection is associated with an almost twofold increase in cancer-related mortality, which may help explain why cancer mortality rates increased at an early stage during the COVID-19 pandemic.

The results are "really quite dramatic," says James DeGregory, an oncologist biologist at the University of Colorado Medical School in Aurora and the author of the study. "Respiratory viral infections did not just awaken cells," he says, they also made them multiply or multiply, "to a huge number."

Reasons for awakening

The researchers found sleeping cancer cells that separated from the original tumor, hiding in tissues such as the bone marrow, in people in remission from breast, prostate and skin cancer, among others. These cells, the precursor of metastases that spread to distant organs, are a problem even for those who have survived these types of cancer. For example, in about a quarter of breast cancer survivors, such cells can cause relapse and metastasis.

Scientists have been trying to find out for a long time what prompts these cells to awaken. Previous works hinted at chronic inflammation as the culprit, for example, caused by cigarette smoking and aging.

DeGregory and his colleagues wondered if acute inflammation caused by a respiratory infection could also reactivate dormant cancer cells. To test this, the researchers genetically designed mice to develop breast tumors similar to those in humans and to seed sleeping tumor cells into other tissues, including lungs. Then they infected the animals with either SARS-CoV-2 or the flu.

Within a few days after infection, dormant cancer cells in the lungs of mice switched to high transmission, multiplied and metastatic lesions formed. But the researchers found out that this did not happen directly because of pathogens: it was a key immune molecule called interleukin-6 (IL-6), which helps accelerate the body's response to extraneous threats. They confirmed that engineering mice do not have IL-6. In these animals, the dorgent cancer cells did not multiply so quickly.

About two weeks after the researchers infected the mice, the cells fell into the drea again. This means that infections do not cause cancer directly, but increase the likelihood that a future threat, be it infection or a genetic mutation, may cause cancer to become active again, says DeGregory. He compared the process with lighting a fire several times. "You woke up the flame, and then it will go out again," he says. "But now you have 100 times more coal than you had before" - which makes it easier to turn into hell.

Nevertheless, this is not the end of the story. The researchers noticed that although IL-6 was necessary to awaken cancer cells, another key immune player, called an auxiliary T-cell, protected cancer cells from other means of protecting the immune system. "Seeing these cancer cells distort the immune system to protect them instead of eliminating them was really quite shocking," DeGregory says.

Population data in large repositories, such as Biobank of Great Britain, helped confirm the results of the study in humans: the increased risk of cancer-related death in those tested positive for COVID-19 was most pronounced in the months immediately after infection, reflecting the rapid spread of newly awakened cancer cells observed in mice.

Viruses and chronic diseases

The results add to the growing work that has linked chronic inflammation caused by pathogens with seemingly unrelated health conditions. For example, infection with the common Epstein-Barr virus increases the risk of multiple sclerosis. But this is the first study showing a link between acute inflammation caused by pathogens and cancer, says Akiko Iwasaki, an immunologist at the Yale School of Medicine in New Haven, Connecticut.

Confirmation of this reference may lead to new treatments and recommendations for cancer survivors, says Mikala Egeblad, an oncologist at the Johns Hopkins School of Medicine in Baltimore, Maryland. For example, doctors used treatments aimed at IL-6 to reduce inflammation in people with severe COVID-19. Future studies should investigate the effectiveness of such drugs in preventing cancer recurrence, she says.

According to DeGregory, until scientists give more answers, cancer survivors are advised to take additional precautions to avoid respiratory infections and consider vaccination against pathogens such as SARS-CoV-2 and the influenza virus.

He and his colleagues plan to study next time whether the results apply to other types of cancer, tissues outside the lungs and other common pathogens.