The ongoing COVID-19 pandemic has posed numerous challenges to healthcare systems worldwide. One major concern is the impact of the virus on individuals with pre-existing medical conditions. Researchers at South Korea’s Sungkyunkwan University School of Medicine have been investigating the relationship between COVID-19 and lung cancer. Their findings suggest that the SARS-CoV-2 Spike (S) protein may induce lung cancer migration and invasion in a Toll-like receptor 2 (TLR2)-dependent manner, providing insights into a potential link between COVID-19 and lung cancer progression.
Previous studies and reports have already shown that SARS-CoV-2 can either cause the progression of various cancers or even initiate and develop cancers. This information can be found in the repository of Thailand Medical News, which contains over 27,000 carefully selected articles and reviews of COVID-19 studies and developments.
Patients with lung cancer are at a higher risk of experiencing severe COVID-19 symptoms, leading researchers to investigate the molecular and cellular mechanisms underlying this vulnerability. The SARS-CoV-2 Spike protein plays a crucial role in triggering hyper-inflammation in epithelial cells and macrophages through Toll-like receptor (TLR) signaling pathways. Specifically, TLR1/2 and TLR2/6-dependent nuclear factor-kappaB (NF-κB) pathways are involved in this process.
To understand the relationship between SARS-CoV-2 susceptibility and lung cancer severity, the researchers analyzed data from non-small cell lung cancer (NSCLC) patients. They focused on the expression of angiotensin-converting enzyme 2 (ACE2) and TLR2 in lung tumor tissues compared to matched normal tissues. ACE2 is associated with SARS-CoV-2 infection, while TLR2 is linked to the hyper-immune response. Their analysis revealed that lung tumor tissues with elevated ACE2 and TLR2 expression showed enrichment in gene sets related to cancer progression, SARS-CoV-2 infection, and TLR signaling, indicating a potential connection between elevated ACE2 and TLR2 expression in lung cancer tissues and disease severity.
The researchers further examined the expression of other factors involved in SARS-CoV-2 infection, including transmembrane protease serine subtype 2 (TMPRSS2), TLR1, and TLR6. These proteins form TLR1/2 or TLR2/6 heterodimers, contributing to the virus’s virulence and pathogenesis. The analysis revealed gene sets associated with cancer progression and inflammatory responses that were significantly enriched in lung tumor tissues with elevated expression of these factors, indicating a potential interplay between SARS-CoV-2-related factors and lung cancer progression.
The SARS-CoV-2 virus induces the production of inflammatory cytokines and chemokines through TLR2-dependent activation of the NF-κB pathway. Lung tumor tissues with elevated expression of ACE2, TMPRSS2, TLR1, TLR2, and TLR6 were associated with gene sets related to inflammatory cytokines and chemokines, further suggesting a connection between SARS-CoV-2 susceptibility and lung cancer severity.
To directly assess the impact of the SARS-CoV-2 Spike protein on lung cancer progression, the researchers conducted experiments on lung cancer cell lines. They treated the cells with the SARS-CoV-2 Spike protein and TLR agonists, and the results showed enhanced migration, invasion, colony-forming ability, and cell proliferation in response to these treatments. Furthermore, phosphorylation of key proteins involved in the NF-κB pathway and elevated cytokine levels were observed.
To confirm the role of TLR2, the researchers generated TLR2-knockout lung cancer cells using the CRISPR-Cas9 gene-editing method. The control cells showed enhanced migration and invasion in response to the SARS-CoV-2 Spike protein and TLR agonists, while the TLR2-knockout cells exhibited significantly reduced migration and invasion, highlighting the critical role of TLR2 in these processes. Additionally, the TLR2-knockout cells displayed reduced production of inflammatory cytokines compared to control cells when exposed to the SARS-CoV-2 Spike protein and TLR agonists. The use of an inhibitor further inhibited migration and invasion in both control and TLR2-knockout cells.
In conclusion, the research conducted at Sungkyunkwan University School of Medicine provides valuable insights into the potential link between SARS-CoV-2 and lung cancer progression. Individuals with upregulated ACE2, TMPRSS2, TLR1, TLR2, and TLR6 in lung cancer tissues may be more susceptible to SARS-CoV-2 infection and experience more severe disease outcomes. TLR2-dependent activation of NF-κB plays a role in promoting lung cancer progression in response to the SARS-CoV-2 Spike protein. However, the role of TLR2 in lung tumor progression remains controversial and requires further research to fully understand its involvement in different stages of lung cancer. Nonetheless, this study contributes significantly to our understanding of how SARS-CoV-2 infection can influence lung cancer progression and may aid in identifying susceptibility factors in lung cancer patients. The study was published in the peer-reviewed journal Cancer Communications.