Impact of SARS-CoV-2 Membrane Protein on Extracellular Vesicles in Breast Cancer Tumor Microenvironment: Implications for Stem Cell Regulation

0
238

The coronavirus disease 2019 (COVID-19) pandemic has imposed significant challenges, especially for vulnerable populations like cancer patients. Studies have highlighted an increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among cancer patients, particularly those with breast cancer. Previous pan-cancer studies have underscored the heightened risk of SARS-CoV-2 infection in this cohort.

Notably, TMPRSS2, a gene associated with SARS-CoV-2 infection, exhibits high expression in breast cancer patients, correlating with poor prognosis. Concurrently, breast cancer patients with COVID-19 often present elevated serum cancer biomarker levels, suggesting a potential interplay between SARS-CoV-2 infection and tumorigenesis.

Numerous investigations have elucidated the augmented risk of adverse outcomes in breast cancer patients with COVID-19, primarily attributed to systemic inflammatory cytokine storms and exacerbated malignancy, leading to metastasis and mortality. Despite the pandemic’s containment, the lingering post-COVID-19 syndrome raises substantial concerns among cancer patients, including those with breast cancer. Post-recovery, SARS-CoV-2 viral proteins persist in patient sera, prompting investigations into their effects on cancer cells and the tumor microenvironment (TME), which fosters tumor development.

In our prior research, we demonstrated that the SARS-CoV-2 membrane protein (M-protein) accentuates the malignancy of triple-negative breast cancer (TNBC). However, the impact of M-protein-induced TNBC on non-cancerous cells within the TME remains poorly understood.

Within the TME, cellular communication occurs through direct cell-cell contact and paracrine signaling, with extracellular vesicles (EVs) playing a pivotal role. EVs, lipid bilayer-bound vehicles containing signaling proteins, RNA, and DNA, facilitate intercellular communication and modulate signaling pathways, thereby influencing tumor progression. While the effects of SARS-CoV-2 proteins on cancer cells have been extensively studied, their impact on cancer cell-derived EVs remains elusive.

The TME encompasses diverse cell types, including fibroblasts, immune cells, endothelial cells, and tissue stem cells like mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs). MSCs derived from adipose tissues have been implicated in supporting TNBC metastasis, undergoing phenotypic changes within the TME. Similarly, EPCs contribute to tumor growth and angiogenesis, crucial for nutrient supply and metastatic dissemination. Notably, MSCs inside the TME support tumor angiogenesis, enhancing the tumorigenic potential of EPCs.

In this study, we investigated how the SARS-CoV-2 M-protein influences EV-mediated regulation of tissue stem cells, including MSCs and EPCs, within the breast cancer TME.

Analyzing the data from previous studies, we identified a clear association between elevated TMPRSS2 expression in breast cancer patients and increased susceptibility to SARS-CoV-2 infection, supported by statistical analyses (p < 0.05). Additionally, the significant rise in serum cancer biomarker levels in breast cancer patients with COVID-19 was observed across multiple studies, indicating a consistent influence of SARS-CoV-2 infection on tumorigenesis (p < 0.01).

Furthermore, our findings elucidate the impact of SARS-CoV-2 M-protein on EV-mediated communication within the breast cancer TME. Through detailed analyses of EV contents and their effects on MSCs and EPCs, we provide novel insights into the modulation of tumor-supportive functions by SARS-CoV-2 proteins.

Overall, this study sheds light on the intricate interplay between SARS-CoV-2 infection, breast cancer biology, and the TME, emphasizing the importance of understanding these interactions in developing effective therapeutic strategies for cancer patients, particularly in the context of emerging infectious diseases like COVID-19.

DISCUSSION – The Impact of SARS-CoV-2 Membrane Protein on Extracellular Vesicles in Breast Cancer Tumor Microenvironment: Implications for Stem Cell Regulation and Tumorigenesis

The discussion surrounding the effects of the SARS-CoV-2 membrane protein (M-protein) on extracellular vesicles (EVs) within the breast cancer tumor microenvironment (TME) is critical for understanding the interplay between viral infection, cancer biology, and tumor progression. This analysis delves into the intricate mechanisms through which M-protein-induced EVs modulate the behaviors of breast tissue stem cells, particularly adipose tissue-derived mesenchymal stem cells (ATMSCs) and endothelial progenitor cells (EPCs), contributing to tumorigenesis and metastasis.

Numerous studies have highlighted the heightened risk of cancer progression, metastasis, and mortality among cancer patients, particularly those with breast cancer, during the COVID-19 pandemic. Notably, previous research has demonstrated the enhanced migratory ability and metastatic potential of breast cancer cells induced by the SARS-CoV-2 M-protein. However, while studies have explored the effects of SARS-CoV-2 infection on the TME, the impact of viral proteins on the interactions between cancer cells and non-cancerous cells within the TME remains understudied.

EVs play a crucial role in mediating cellular communication within the TME, influencing tumor progression and metastasis. Despite extensive research on the effects of SARS-CoV-2 proteins on cancer cells, their impact on cancer cell-derived EVs has not been fully elucidated. Building upon previous findings of M-protein-induced malignancy in triple-negative breast cancer (TNBC), this study investigated the effects of M-protein on EVs derived from TNBC and their subsequent influence on ATMSCs and EPCs.

The analysis revealed distinct effects of M-protein-induced EVs (MpEVs) on recipient cells compared to EVs derived from untreated TNBC. MpEVs exhibited a higher induction of proliferation and cytokine gene expression in recipient TNBC cells, underscoring the altered functional properties of EVs in response to M-protein stimulation. Moreover, MpEVs facilitated the paracrine effects of ATMSCs, promoting migration, metastasis, and stemness characteristics in non-aggressive TNBC cells, accompanied by increased prostaglandin E2 (PGE2) secretion.

Furthermore, MpEVs influenced the behavior of EPCs, promoting their angiogenic abilities and differentiation into tumor endothelial cell-like phenotypes. This resulted in enhanced angiogenesis, metastasis, and stemness characteristics in TNBC cells, facilitated by the upregulation of specific angiogenic and metastatic genes.

Notably, the study revealed the involvement of PGE2 signaling in MpEV-mediated effects on ATMSCs and non-aggressive TNBC cells, highlighting the intricate signaling networks within the TME. Additionally, MpEV-primed ATMSCs displayed characteristics reminiscent of tumor-associated MSCs (TA-MSCs), suggesting a potential acquisition of TA-MSC-like properties under M-protein influence.

The investigation extended to elucidate the impact of MpEVs on EPCs, uncovering their enhanced angiogenic potential and differentiation into tumor endothelial cell-like phenotypes. MpEV-primed EPCs exhibited increased expression of angiogenic and metastatic genes, correlating with augmented tumor angiogenesis, progression, and metastasis.

Moreover, the study explored the role of ATMSCs in the TME, revealing their contribution to MpEV-mediated effects on EPCs and tumor progression. ATMSCs promoted EPC-mediated angiogenesis and tumor progression in response to MpEVs, underscoring the complex crosstalk between different cell types within the TME.

Overall, the findings underscore the multifaceted influence of M-protein-induced EVs on the breast cancer TME, highlighting the modulation of stem cell behaviors and tumor progression. The study sheds light on the intricate interplay between viral infection, cancer biology, and the TME, emphasizing the need for further research to elucidate these complex interactions and develop targeted therapeutic strategies for breast cancer patients, particularly in the context of emerging infectious diseases like COVID-19.


REFERENCE LINK : https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1346312/full

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.