The breathing viruses arouse dormant breast cancer cells and increase the risk of recurrence

In the last study published in An international team of scientists has shown that respiratory viral infections arouse sleeping cells of breast cancer in the lungs.

Breast cancer is the most widespread cancer in women and the second leading cause of cancer -related deaths in the United States (USA). Widespread cancer cells (DCC) may remain dormant for years after the initial remission before metastatic recurrence. Tumor microenvy and cellular-contactic factors determine whether the metastatic cells are progressing or dormant. In particular, microenvil disorders may be sufficient to increase metastasis.

A breath viral infections are common, and seasonal flu affects over a billion people a year. These infections are usually associated with the pulmonary inflammation with the increase in inflammatory cytokines (interferons [IFNs] and interleukin 6 [IL-6]) and expansion of immune cells such as macrophages, T cells and neutrophils. Such inflammatory mechanisms were reported as a metastatic process regulators.

Examination and results

In this study, scientists have examined the impact of respiratory viral infections on sleeping breast cancer in mice. First of all, they used mice, DCC, MMTV-HER2 breast sleeping model, to examine the influenza A (IAV) virus influence on the awakening of DCC sleep. Mice was infected in terms of a deadly dose of IAV; Both MMTV-Her2 and wild type mice showed comparable inflammatory response kinetics and viral slack.

The lungs were collected at several time points and assessed in terms of abundance of the human receptor of the 2-well-growing factor (HER2+). Several insulated DCC or DCC clusters were detected before the infection. Nevertheless, the metastatic load increased by up to 1000 times between three and 15 days after infection (DPI). The number of HER2+ cells remained raised at 28 and 60 dpi and was still detected nine months later.

There were no changes in Ki67+ HER2+ cells in the mammary glands, and QPCR blood samples did not show growth of circulating cancer cells, which suggests that the growth of HER2+ cells in the lungs does not come from increased vaccination of cancer cells in the mammary glands.

In addition, the band observed a significant growth of HER2+ cells expressing KI67 at 3 DPI. Although HER2+ expressing cells Ki67 decreased by 15 dpi, the number of these cells remained increased at 60 dpi compared to the initial value.

DCC dormant maintain a state similar to mesenchymal (positive wimentine) and undergo epithelial shift (positive adhesive molecule of the epithelial cells [EpCAM+]) During the sleep. The most dormant DCC in uninhabited lungs is Wimentine+. While the percentage of Wimentine+ HER2+ cells had no effect early in infection (3 to 6 dpi), it dropped to 50% by 9 dpi and less than 20% per 28 dpi. However, the HER2+ cell fraction showed EPCAM expression by 3 dpi.

In addition, while most HER2+ cells lost the positive EPCAM positiveness after 6 dpi, the percentage of EPCAM+ HER+ cells remained increased. Thus, IAV infection caused a temporary epithelial shift, creating a unique hybrid and proliferative phenotype, which retained a certain expression of the mesenchymal marker, enabling DCC awakening.

RNA-seq analyzes showed activation of inflammatory (IL-6-JAK-STAT3), angiogenesis and non-cell remode routes, including collagen network and metaloproteinase activity, which is known to confirm tumor growth.

The authors also reported changes in the tumor microenvil, including lesions of extracellular matrix and angiogenic signaling, which can help maintain awakened DCC. The team also noticed the activation of the IL-6 signal trail in DCCS after infection. Further studies have shown that the IL-6 triggered infection was crucial in mediation in the initial DCC sleep.

Scientists have identified a two-phase process: first, IL-6 drives a switch from mesenchymal to a hybrid phenotype and fuel rapid expansion; Later, after recruitment of T cells, CD4+ cells maintain the awakened DCC population. During the second phase of the CD4+ cells, they partly maintain DCC, suppressing the CD8+ immune answers.

Profiling gene expression revealed that CD4+ in mice containing cancer had a reduced content of mitochondria, deviation towards the phenotype of memory and a lower effector function, additionally limiting the cytotoxicity of CD8+.

The study also showed that the exhaustion of CD4+ cells restored the content of CD8+ cell mitochondria and effector activity, leading to a more effective elimination of DCC.

Then the team examined whether Coronavirus 2019 (Covid-19) can wake up sleeping DCC. For this purpose, heavy Coronavirus 2 (SARS-COV-2) strain was used to mouse. The MA10 infection caused the production of IFNα and IL-6 in the lungs.

In addition, the infection MA10 caused a significant growth of HER2+ cells by 28 dpi. In addition, there was a gradual increase in the number of HER2+ cells and Ki67+ HER2+ cells after MA10 infection, with a reduction of vimentine positivity and a temporary increase in EPCAM positivity. Consistently, these changes required IL-6, because the changes related to the MA10 infection were significantly reduced in mice with IL-6 knockout.

In addition, scientists analyzed data from the UK Biobank (UKB) in order to assess whether a positive SARS-COV-2 test was associated with a higher risk of mortality among people who survived cancer. The UKB population was followed by December 2022, which included 4,837 people with diagnosis of cancer before 2015, 413 deaths were registered. They covered 115 and 298 deaths, who properly tested positive and negative for SARS-COV-2, giving a quotient of opportunities (OR) of 4.5.

Even after the exclusion of deaths from Covid-19, positive testing people still had a higher mortality from 2.56. There was an almost double increase in mortality due to cancer (OR: 1.85) in people with a positive test compared to test participants.

The data showed that the link was the strongest in the months immediately after infection and weakened over time, reflecting the early rapid expansion of DCC observed in mouse models. The team observed an increased risk for all causes, insolence-18 and mortality from cancer among participants who have positively checked SARS-COV-2 compared to those who tested negative.

Finally, the Flatiron Health database was applied to assess whether women with breast cancer experienced a higher risk of metastatic progress to the lungs after Covid-19. Women with Covid-19 after diagnosis of breast cancer had a risk ratio of 1.44 to a later diagnosis metastatic breast canceradapted to the age, race and ethnic origin. After additional adaptation of the subtype of breast cancer and comorbidities, the risk factor was 1.41 and was no longer statistically significant, although the direction of the effect was consistent.

Conclusions

The results indicate that respiratory viral infections are conducive to awakening and expansion of sleeping cancer cells. Depending on IL-6, the transition from mesenchymal to a hybrid phenotype promotes expansion, and then the establishment of CD4+niches, which inhibit the elimination of DCC.

These niches also disturb the CD8+ anti -cancer activity by changing the metabolism of immune cells and effector potential. Other populations of immune cells, including macrophages, have also shown shifts of the phenotype towards cancer support.

In general, these data reveal how the lung viral infections increase the risk of recurrence of cancer, while both the mouse and human data show the greatest risk in the early period after infection, emphasizing the need for a strategy to mitigate an increased risk associated with progression.