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Researchers at the University of Colorado Anschutz Medical Campus, Montefiore Einstein Comprehensive Cancer Center (MECCC) and Utrecht University have discovered the first direct evidence that common respiratory disorders can awaken dormant breast cancer cells that have spread to the lungs. The findings, published in Nature, were based on mice studies and supported by data showing increased cancer-related mortality and metastatic lung disease among cancer survivors infected with SARS-CoV-2.

“Our findings indicate that individuals with a history of cancer may benefit from taking precautions against respiratory viruses, such as vaccination when available, and discussing any concerns with their healthcare providers,” said Dr Julio Aguirre-Ghiso, co-leader of the study and director of MECCC’s Cancer Dormancy Institute.

How viruses awaken ‘sleeper cells’

Prior evidence suggested that inflammatory processes might awaken disseminated cancer cells (DCCs) – cells that spread from a primary tumour to distant organs and often lie dormant for years.

“During the COVID-19 pandemic, anecdotal reports suggested a possible increase in cancer death rates, bolstering the idea that severe inflammation might contribute to arousing dormant DCCs,” said Dr Aguirre-Ghiso.

Using unique mouse models of metastatic breast cancer with dormant DCCs in the lungs, researchers exposed the mice to SARS-CoV-2 and influenza viruses. Both infections triggered the awakening of dormant DCCs – leading to a fast expansion of metastatic cells within days and visible metastatic lesions within two weeks.

“Dormant cancer cells are like the embers left in an abandoned campfire, and respiratory viruses are like a strong wind that reignites the flames,” said senior author and deputy director of CU Cancer Center Dr James DeGregori.

Molecular analysis revealed that interleukin-6 (IL-6) – a protein released by immune cells during infections or injury – was a key driver of this process.

“The identification of IL-6 as a key mediator in arousing DCCs from dormancy suggests that using IL-6 inhibitors or other targeted immunotherapies might prevent or lessen the resurgence of metastasis following viral infection,” said Dr Aguirre-Ghiso.

Human data support the findings

The COVID-19 pandemic allowed researchers to investigate this mechanism in human populations. The team analysed two large datasets and found that respiratory virus infections in cancer survivors were linked with an increased risk of metastasis.

Using the UK Biobank – which follows more than 500,000 participants – researchers examined cancer survivors diagnosed at least five years prior to the pandemic. Among the 487 individuals who tested positive for COVID-19 –compared with 4,350 matched controls who tested negative – those with prior COVID-19 infections were nearly twice as likely to die from cancer. “The effect was most pronounced in the first year after infection,” said Dr Roel Vermeulen.

Similarly, data from the US Flatiron Health database showed that female breast cancer patients who contracted COVID-19 were almost 50 percent more likely to experience lung metastases compared to those who were COVID-19 negative.

“Our findings suggest that cancer survivors may be at increased risk of metastatic relapse after common respiratory viral infections,” said Dr Vermeulen. “It is important to note that our study focused on the period before COVID-19 vaccines were available.”

Looking ahead

The researchers emphasise the need for further study. “By understanding underlying mechanisms, we will work hard to develop interventions that can limit the risk of metastatic progression in cancer survivors who experience respiratory viral infections,” said Dr DeGregori. “We also plan to extend our analyses, both in animal models and through mining of clinical data, to other cancer types and other sites of metastatic disease.”

These findings show the importance of preventive measures, such as vaccination and could start the process toward new therapies targeting the inflammatory pathways involved. As the researchers continue to investigate this link across other cancer types, it highlights the need for heightened awareness for cancer survivors facing common viral infections.

“Respiratory viral infections are forever a part of our lives, so we need to understand the longer-term consequences of these infections,” DeGregori concluded.

The possibility of having a tool that facilitates population screening for Chronic Obstructive Pulmonary Disease (COPD) is getting closer. A multicenter study involving leading hospitals across Spain, led by Hospital del Mar and its research institute, has confirmed that people with COPD show altered levels of specific metabolites in their blood. This finding may make it possible to use these biomarkers to identify, at an early stage, those likely to have COPD. The study, conducted with researchers from the CIBER Respiratory Diseases (CIBERES) and Epidemiology and Public Health (CIBERESP) areas, has been published in the International Journal of Molecular Sciences.

This could serve as a screening method to define high-risk populations for COPD, who could then be referred for the definitive diagnostic test, spirometry.”

Dr. Joaquim Gea, Emeritus Head of the Pulmonology Service at Hospital del Mar and Coordinator of the Myogenesis, Inflammation, and Muscle Function Research Group at the Hospital del Mar Research Institute

Currently, 70% of COPD cases are underdiagnosed, largely due to the difficulty of correctly performing the reference test-spirometry-on a population scale. This leads to late or missed diagnoses, which delay the start of treatment and result in patients reaching care with advanced disease. It also increases the risk of COPD-associated conditions such as lung cancer.

Ten altered metabolites

The study analyzed data from 91 COPD patients and 91 healthy controls. All participants underwent blood tests, which were analyzed using mass spectrometry to detect metabolite levels. Of the 360 molecules identified, about 50 were selected as the most relevant. Using artificial intelligence, researchers pinpointed the ten best-performing metabolites in combination for identifying individuals with COPD.

The results showed these metabolites had very high sensitivity and specificity-over 90%- in distinguishing COPD patients from healthy individuals. These molecules are linked to energy production, which may explain fatigue and other limitations experienced by COPD patients, as well as lipid metabolism, which could relate to the cardiovascular comorbidities often found in these individuals. The findings suggest that COPD patients have a reduced capacity to produce energy and altered lipid metabolism

El hecho de seleccionar un grupo reducido de marcadores puede ayudar a su implantación en un programa de cribado poblacional en EPOC. Además, su aplicación puede ser relativamente sencilla, al poderlos detectar con un análisis de sangre rutinario. Como explica el Dr. Gea, esto “nos puede permitir tener una herramienta para la detección precoz de las personas con EPOC, hecho que implica el inicio del tratamiento en un momento inicial de la enfermedad y una vigilancia más estrecha de las posibles comorbilidades”.

Focusing on a limited group of biomarkers could facilitate their inclusion in a population screening program for COPD. Moreover, their application could be relatively straightforward, as they can be detected through a routine blood test. As Dr. Gea points out, this “could give us a tool for early detection of individuals with COPD, which would allow treatment to begin in the early stages of the disease and enable closer monitoring of potential comorbidities.”

The next step in this line of research is to verify the efficacy of these biomarkers in a larger and more diverse population. If successful, this could pave the way for their implementation in clinical practice.