Respiratory viruses awaken cancer cells from the sleeping breast and increase the risk of relapse

New research reveals how current respiratory viruses can return cancer cells from dormant breast in growth mode, discovering an immune path that increases the risk of relapse and pointed out towards new prevention strategies.

Study: respiratory viral infections awaken cancer cells in the metastatic breast in the lungs. However, Image credit: Crystal Light / Shutterstock

In a recent study published in NatureAn international team of researchers has shown that respiratory viral infections awaken breast cancer cells in the lungs.

Breast cancer is the most widespread cancer in women. For example, the second cause of death-related deaths in the United States respiratory viruses awaken cancer cells (United States). However, Disseminated cancer cells (DCC) can remain dormant for years after initial remission before the metastatic relapse. In addition, Tumor microenvironnement and cellular intrinsic factors determine if metastatic cells are progressing or remaining dormant. Similarly, In particular, microenvironmental disturbances may be sufficient to increase metastases.

The respiratory viral infections are common, the seasonal flu affecting more than a billion people each year. Therefore, These infections are generally associated with pulmonary inflammation as well as an increase in inflammatory cytokines (interfeons (IFN). Meanwhile, interleukin 6 (IL-6)) and the expansion of immune cells, such as macrophages, T cells and neutrophils. Moreover, Such inflammatory mechanisms have been reported as regulators of metastatic processes.

Study. Furthermore, results

In this study, researchers have examined the effects of respiratory viral infections on dormancy of breast cancer in mice. For example, First of all. In addition, they used a dormancy mouse model DCC breast, MMTV-Her2, respiratory viruses awaken cancer cells to explore the effects of the A (IAV) virus on the awakening of DCC dormants. In addition, The mice have been infected with a subletal dose of the IAV. Additionally, In addition, MMTV-Her2 and wild mouses have shown a comparable inflammatory response and viral clearance kinetics.

The lungs were collected at several times. Nevertheless, evaluated for the abundance of positive 2 receptor cells (HER2 +) of the human epidermal growth factor. Before the infection, some DCCs or isolated clusters of DCC were detected. However, the metastatic burden has increased up to 1,000 times between three and 15 days after infection (DPI). The number of HER2 + cells remained high at 28 and 60 DPI and was still detectable nine months later.

There was no change in the Ki67 + HER2 + cells in the mammary glands. and the QPCR of blood samples has shown no increase in cancer cells in respiratory viruses awaken cancer cells circulation, which suggests that the increase in HER2 + cells in the lungs was not derived from the high sowing of cancer cells in the mammary glands.

In addition, the team observed a significant increase in HER2 + cells expressing Ki67 to 3 DPI. Although the HER2 + cells expressing Ki67 decreased by 15 DPI. the number of these cells remained high at 60 dpi compared to the basic line.

Dorting DCCs maintain a mesenchymal type (positive vimentine). suffer an epithelial offset (adhesion molecule of positive epithelial cells (EPCAM +)) during the output of the dormancy. Most DCC dormants in the uninfected lungs were vimentine +. Although the percentage of vimentine + her2 + cells was not affected early in the infection (3 to 6 DPI). it decreased to 50% per 9 DPI and less than 20% per 28 DPI. On the other hand, a fraction of the HER2 + respiratory viruses awaken cancer cells cells showed the expression of EPCAM by 3 DPI.

In addition. while most HER2 + cells have lost the positivity of EPCAM after 6 DPI, the percentage of EPCAM + HER + cells has remained high. Thus. IAV infection has induced a transient epithelial shift, creating a unique hybrid and proliferative phenotype which has retained a mesenchymal marker expression, allowing a DCC sleeping awakening.

RNA-SEQ analyzes have shown that activation of inflammatory pathways (IL-6-JAK-stat3). angiogenesis and renovation paths of extracellular matrix, including the retication of collagen and the activity of metaloproteinase, which are known to support tumor growth.

The authors also reported changes in tumor microenvironment. including changes in extracellular matrix and angiogenic signaling, which could help keep the DCC awake. The team also noted the activation of the IL-6 signaling pathway in the DCCS after the infection. Additional investigations said that the IL-6 launched by the infection was the respiratory viruses awaken cancer cells key to the initial awakening of DCC dormant.

The researchers have identified a biphase process: first. IL-6 leads to the passage of a mesenchymal phenotype to a hybrid phenotype and feeds a rapid expansion; Later, after recruiting T cells, CD4 + T cells support the awake DCC population. During this second phase, CD4 + cells partially maintain the DCCs by removing CD8 + immune responses.

The profiling of the expression of the genes revealed that CD4 + cells in mice carrying tumors had reduced the mitochondrial content. a bias to a memory phenotype and a lower effective function, more limiting CD8 + cytotoxicity.

The study also revealed that the exhaustion of CD4 + cells restored the mitochondrial content of CD8 + cells. the effective activity, leading to a more effective elimination of DCCs.

Then the team studied if the 2019 Coronavirus disease (COVVI-19) can arouse DCC dormants. To this end, respiratory viruses awaken cancer cells a strain 2 (SARS-COV-2) of the severe acute respiratory syndrome adapted to the mouse (MA10) has been used. MA10 infection triggered the production of Ifnα and IL-6 in the lungs.

In addition, MA10 infection has led to a significant increase in Her2 + cells by 28 DPI. In addition. there has been a steps increase in the number of HER2 + cells and Ki67 + HER2 + cells after a MA10 infection, with reductions in vimentine positivity and transitional increases in the positivity of EPCAM. Consistently. these changes required the IL-6, because the changes associated with the MA10 infection have been significantly reduced in the Knockout IL-6 mice.

In addition. researchers have analyzed the data from the Biobank United Kingdom (UKB) to assess whether a positive SARS-COV-2 test has been associated with a higher risk of mortality in cancer survivors. In a UKB population, followed until December 2022, which included respiratory viruses awaken cancer cells 4,837 people with a cancer diagnosis before 2015, 413 deaths were recorded. These included 115. 298 deaths, those which were tested positive and negative for the Sras-Cov-2, respectively, giving a rating of ratings (gold) of 4.5.

Even after having excluded the deaths attributed to COVID-19, positive individuals to tests still had higher mortality, with a 2.56 gold. There has been an increase in cancer mortality almost twice (gold: 1.85) in positive individuals compared to participants in negative tests.

The data has shown that the association was the strongest in the months immediately after the infection. has weakened over time, reflecting the early rapid expansion of the DCCs observed in mouse models. The team has observed high risks for all causes of all causes. non-comfortable and cancer mortality in participants who were tested positive for the SRAS-COV-2 compared to those who tested negative.

Finally. the Flatiron Health database was used to respiratory viruses awaken cancer cells assess whether women with breast cancer have experienced a higher risk of metastatic progression to the lungs after COVVI-19. Women with covid-19 after a diagnosis of breast cancer had a risk ratio of 1.44 for the subsequent diagnosis of metastatic breast cancer, adjusted for age, race and ethnicity. After an additional adjustment for the breast cancer subtype and comorbidities, the risk ratio was 1.41 and is no longer statistically significant, although the effective management is consistent.

Respiratory viruses awaken cancer cells

Conclusions

The results indicate that respiratory viral infections promote the awakening. expansion of dormant cancer cells. A switch dependent on the IL-6 of a mesenchymal state to a hybrid phenotype promotes expansion. followed by the establishment of CD4 + niches which inhibit the elimination of the DCC.

These niches also hamper the activity of CD8 + by modifying the metabolism of immune cells and the effective potential. Other immune cell respiratory viruses awaken cancer cells populations, including macrophages, have also shown changes in phenotype to a state of support for tumors.

Overall. these data reveal how pulmonary viral infections increase the risk of recurrence of cancer, mouse and human data showing the greatest risk at the start of the infection, highlighting the need for strategies to mitigate the increased risk of associated metastatic progression.