BREAKING! SARS-CoV-2 Causes Aggressive Breast Cancer Progression And Manipulates Tissue Stem Cells In The Tumor Microenvironment!

COVID-19 News: The COVID-19 pandemic has left an indelible mark on global health, with its repercussions reaching far beyond the immediate threat of viral infection. Cancer patients, particularly those with breast cancer, have emerged as a vulnerable group, facing increased susceptibility to SARS-CoV-2 infection and experiencing worse outcomes. Recent studies have highlighted the elevated risk of accelerated cancer progression, metastasis, and mortality in breast cancer patients infected with the virus.


SARS-CoV-2 Causes Aggressive Breast Cancer Progression
Proposed model: In TME, SARS-CoV-2 M-protein-induced BCC recruit and control the activity of ATMSC and EPC via EV which facilitate the development and metastasis of breast tumors.
 
This investigative study by researchers from University of Tsukuba-Japan that is covered in this COVID-19 News report delved into the intricate interplay between SARS-CoV-2 and breast cancer and unveiled a groundbreaking revelation: the viral infection, specifically through its membrane protein (M-protein), appears to play a pivotal role in promoting the aggressiveness of triple-negative breast cancer cells (triple-negative BCC). This discovery opens a new chapter in the understanding of the complex dynamics within the tumor microenvironment (TME) and its influence on cancer progression.

Thailand Medical News had already earlier warned that SARS-CoV-2 infections can lead to increased risk of breast cancers and breast cancer metastasis.
 
https://www.thailandmedical.news/news/breaking-covid-19-news-sars-cov-2-infections-lead-to-increased-risk-of-breast-cancer,-recurrence-of-breast-cancer-and-also-breast-cancer-metastasis

Methodology
Building upon prior research on the malignant transformation induced by SARS-CoV-2 M-protein in triple-negative BCC, this study delves deeper into the effects of M-protein on extracellular vesicles (EV) derived from these cancer cells. These EVs act as carriers, facilitating communication between cancer cells and neighboring non-cancer cells within the TME. Specifically, the study team explored the impact of M-protein-induced EVs (MpEV) on tissue stem cells, including adipose tissue-derived mesenchymal stem cells (ATMSC) and endothelial progenitor cells (EPC), shedding light on their role in fostering a microenvironment conducive to tumor progression.
 
Results
The study findings demonstrate that MpEV significantly enhance the paracrine effects of ATMSC on non-aggressive BCC. This augmentation includes the promotion of migration, in duction of stemness phenotypes, and increased in vivo metastasis, primarily mediated by the PGE2/IL1 signaling pathways. Moreover, MpEV exerted similar effects on EPC, inducing a tumor endothelial cell-like phenotype with heightened angiogenesis capabilities. The ability of EPC to support the aggressiveness and metastasis of non-aggressive BCC was notably enhanced after uptake of MpEV.
 
Discussion
The implications of the study results suggest a pivotal role for SARS-CoV-2 M-protein in reshaping cellular communication within the TME through the modulation of EV. By inducing alterations in EV derived from triple-negative BCC, M-protein appears to amplify the functional support provided by non-cancer cells, particularly tissue stem cells, in tumorigenesis. This intricate interplay adds a layer of complexity to the understanding of how viral infections can impact cancer progression.
 
Unraveling the Impact on Breast Cancer Patients
Breast cancer patients, already grappling with the challenges of their diagnosis, face heightened risks and complexities when infected with SARS-CoV-2. The increased expression of TMPRSS2, an infection-associated gene, in breast cancer patients with COVID-19 underscores the interconnectedness of viral infections and cancer progression. Notably, breast cancer patients with COVID-19 exhibit elevated serum cancer biomarker levels, hinting at the potential influence of SARS-CoV-2 infection on tumorigenesis.
 
The long-term post-COVID-19 syndrome poses additional concerns for cancer survivors, necessitating an exploration into the lingering effects of SARS-CoV-2 viral proteins in patient sera. Previous studies revealed the presence of the SARS-CoV-2 M-protein in recovered individuals, prompting an investigation into its effects on cancer cells and the TME. This study builds upon that foundation, unveiling the intricate web of interactions between M-protein, EV, and tissue stem cells that contribute to the support of cancer progression.
 
Role of Extracellular Vesicles in Tumor Microenvironment
The TME is a complex ecosystem comprising cancer and non-cancer cells, including fibroblasts, immune cells, endothelial cells, and tissue stem cells such as mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC). EVs, lipid bilayer-bound vehicles secreted by cells, play a crucial role in mediating cellular communication within this microenvironment. Laden with signaling proteins, RNA, and DNA reflective of their cell of origin, EVs act as messengers, transmitting information between cells and influencing signaling pathways in target cells.

Cancer cells continuously release EVs into the extracellular space, shaping the TME and supporting tumor development. Previous studies have linked the functions of cancer cell-derived EVs in the TME to the aggressiveness of parental cancer cells. In the context of breast cancer, this new study expands this understanding by examining the effects of SARS-CoV-2 M-protein on EV derived from triple-negative BCC.
 
Tissue Stem Cells in the Tumor Microenvironment
In addition to cancer cells, the TME harbors a diverse array of non-cancerous cells, including tissue stem cells such as MSC and EPC. Prior research highlighted the supportive role of ATMSC in promoting the metastasis of triple-negative BCC through paracrine effects. These MSC, derived from adipose tissues, undergo behavior changes in response to cancer signals in the TME, evolving into tumor-associated mesenchymal stem cells (TA-MSC) or cancer-associated fibroblasts (CAF).
 
EPC, belonging to the endothelial lineage, contribute to tumor growth and angiogenesis by facilitating nutrient transport to the tumor core and maintaining metabolic homeostasis. The loose cell-cell connections formed by EPC in tumor blood vessels further facilitate the intravasation of circulating cancer cells, initiating the metastatic process.
 
Impact of SARS-CoV-2 M-Protein on Extracellular Vesicles and Tissue Stem Cells
The study provides compelling evidence that SARS-CoV-2 M-protein induces alterations in the cellular communication between cancer cells and non-cancer cells within the TME via EV. MpEV derived from triple-negative BCC displayed a heightened ability to promote the functions of non-cancer cells, particularly tissue stem cells, in tumorigenesis.
 
Notably, MpEV induced the paracrine effects of ATMSC on non-aggressive BCC, fostering migration, stemness phenotypes, and in vivo metastasis. The involvement of PGE2/IL1 signaling pathways in this process highlights the intricate molecular mechanisms at play. Furthermore, MpEV impacted the characteristics of EPC, endowing them with a tumor endothelial cell-like phenotype that contributed to increased angiogenesis and support for the aggressiveness and metastasis of non-aggressive BCC.
 
Implications for Breast Cancer Patients with COVID-19
The cumulative evidence from our study points towards a dual impact of SARS-CoV-2 infection in breast cancer patients. Beyond exacerbating the aggressiveness of cancer cells themselves, the virus appears to enhance the ability of cancer cells to manipulate the surrounding TME. By unraveling the specific interactions between cancer cells and non-cancer cells, our findings pave the way for a deeper understanding of the underlying mechanisms during COVID-19 infection.
 
Conclusion
In conclusion, our research sheds light on the intricate connections between SARS-CoV-2 infection and breast cancer progression, emphasizing the role of tissue stem cells and EV in the TME. The orchestrated interplay between viral proteins, cancer cells, and non-cancer cells within the TME unveils a complex narrative that warrants further exploration and targeted therapeutic interventions. By elucidating the mechanisms underlying the aggressive phenotype induced by SARS-CoV-2 infection, the findings pave the way for the development of novel treatment strategies that target key players in the TME.
 
Moving forward, it is imperative to translate these findings into clinical applications that benefit breast cancer patients, particularly those susceptible to SARS-CoV-2 infection. This necessitates interdisciplinary collaborations between virologists, oncologists, and immunologists to devise comprehensive approaches that mitigate the adverse effects of viral infections on cancer progression.
 
Moreover, the study underscores the importance of vaccination and infection prevention strategies in cancer care settings. Vaccination against SARS-CoV-2 not only reduces the risk of viral infection and its associated complications but also mitigates the potential impact on cancer progression. Additionally, stringent infection control measures and personalized risk assessment protocols should be implemented to safeguard vulnerable patient populations.
 
As we continue to unravel the complex interplay between viral infections and cancer progression, it is essential to remain vigilant and adaptive in our approach to patient care. By integrating cutting-edge research with clinical practice, we can effectively address the multifaceted challenges posed by the intersection of infectious diseases and cancer. Together, we can strive towards a future where every breast cancer patient receives personalized, comprehensive care that maximizes their chances of survival and quality of life.
 
The study findings were published in the peer reviewed journal: Frontiers in Oncology.
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1346312/full
 
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