Respiratory viruses like influenza promote cancer metastasis

Breast cancer is the most common tumor in women, and the most deadly among them. One of the greatest challenges is not so much addressing the primary tumor, but rather preventing malignant cells from reappearing in another organ years, even decades, later and causing metastasis, which is the cause of the vast majority of cancer deaths.

A study published this Wednesday shows that influenza and other respiratory viruses like SARS-CoV-2 are capable of reactivating these dormant cancer cells and causing metastasis. The work, published in Nature , was conducted by researchers in the US and the UK who analyzed tens of thousands of cancer cases.

A few years ago, Spanish immunologist Mercedes Rincón of the University of Colorado (UC) observed that infection with the flu virus in mice caused a sudden and brutal expansion of cancer cells in the lungs of animals with a primary tumor in the breast. The cause did not seem to be so much the virus itself as the immune system's response to combat it.

In a new round of animal experiments, Rincón's team, along with colleagues from the UC Cancer Center and the Albert Einstein College of Medicine, tested whether infection with another respiratory virus, SARS-CoV-2 , which causes COVID-19, also awakens dormant breast cancer cells in the lungs. The results show that it does: the virus triggers a massive spread of new tumors.

To determine whether the same holds true in humans, researchers analyzed data from nearly 5,000 cancer patients in the UK Biobank . The results show that cancer patients infected with coronavirus have twice the risk of death compared to those who are not infected. Scientists also analyzed another database in the United States of nearly 37,000 breast cancer patients. In this case, they found that coronavirus infection increases the risk of lung metastasis by 50%.

These are "almost unprecedented" data in cancer epidemiology, the authors of the study emphasize in a press release. This finding explains part of the increase in cancer deaths in the first two years of the pandemic, they add.

How dormant cells wake up

Rincón, born 62 years ago in Cenegro, a small town in Soria where she grew up without running water, has spent 30 years in the United States researching the molecule responsible for this awakening of cancer cells. It's called interleukin 6, and its purpose is to provoke inflammation to initiate an immune response to an external attack. When this molecule is produced in a lung where there are dormant cancer cells, its effect is to signal them to wake up and multiply, which reactivates the cancer. "In studies with mice, we have shown that if we block this molecule, lung metastasis does not occur," explains the immunologist via teleconference. The researcher has dedicated almost her entire career to studying the role of this molecule in allergies, autoimmune diseases such as rheumatoid arthritis, and cancer.

There are several approved drugs that block interleukin 6 and other molecules related to it, among other things, to treat severe COVID-19, Rincón points out. These studies provide a solid foundation linking respiratory viruses and metastasis. The next step would be to test the available drugs in specific clinical trials, she points out. “For now, we've only looked at influenza and COVID-19, but we've already started another project to study whether other infections, respiratory or not, promote metastasis in other tissues, for example, the liver,” the immunologist adds.

Javier De Castro , vice president of the Spanish Society of Medical Oncology (SEOM), highlights the value of this study. “During COVID, we focused heavily on the weakened immune system and the use of antibiotics as a possible trigger for cancer, especially in patients with very advanced metastatic tumors,” he explains. “We also saw an increase in mortality due to delayed medical care. This article now shows us how these dormant cells can be activated by the infection process.” The head of Oncology at La Paz Hospital in Madrid sees a possible future application of this finding: “Giving cancer survivors vaccines or anti-inflammatory drugs that can prevent the inflammatory response and tumor cell activation.”

A new vision of metastasis

Molecular biologist José María Adrover believes this new data is "relevant because these are very common respiratory infections." Adrover, a 41-year-old from Madrid who directs his own research group at the Francis Crick Institute in London, believes that "this same process probably occurs in other tumors that cause metastasis to other organs." He also emphasizes that in recent years, the prevailing idea that metastasis is a late process has been challenged. In contrast to this view of a tumor that grows and then, when it is very large, begins to disseminate these cells, which reach other organs, this researcher explains that "for some time now, it has been clearer that this is not the case; that cancer begins to release these cells throughout the body early, and they remain dormant there, waiting for the moment to awaken."

Adrover's team has just published another study that has revealed a new role for the immune system in enhancing tumor aggressiveness. The study, also published in Nature , shows that cancer connects with the bone marrow to hijack its ability to produce blood stem cells. Tumors thus produce a new lineage of neutrophils, a type of immune system cell, which swarm into blood vessels, causing blockages that result in the death of the surrounding tumor tissue. These lesions, known as necrosis, were until now thought to be a passive consequence of cancer growth, but Adrover's team has demonstrated a leading role in metastasis. In their study, they demonstrate several ways to slow this process, one of them using disulfiram , a drug already approved for the treatment of alcoholism. "Metastasis is the major problem we cancer researchers face, and thanks to these advances, we are beginning to have targets to address," he emphasizes.

Previous studies have already shown that influenza promotes primary tumors in the skin and lungs. These new findings present viruses as promoters of cancer in other organs, even when the infection has already been eliminated from the body. “This discovery should make us reconsider whether we need to test people whose cancer is in remission during respiratory virus season to see if dormant cells have been reactivated,” write Brooke Dresden and John Alcorn , immunologists at Children's Hospital of Pittsburgh, in an opinion published alongside the study.

After more than 30 years working as a scientist in the United States, Rincón is considering applying for US citizenship for the first time. Until now, she hadn't had any problems with her work permit, a green card , but things have changed with the government's new immigration policies. "I used to travel to Spain every year during the summer and Christmas to visit family, but I won't be doing so this year because there have already been cases of people with work permits who have ended up deported. If things don't change, I'd even consider returning to Spain and starting over there," she says.