Signal Transduction and Targeted Therapy | COVID-19 Triggers Pulmonary Tumor Outgrowth through Hypoxia- and Inflammation-Induced VEGF-Dependent Angiogenesis

This study elucidates how SARS-CoV-2 infection activates the VEGF signaling pathway by remodeling the microenvironment, providing critical experimental evidence for early lung cancer screening and combination anti-angiogenic therapeutic strategies.

 

Literature Overview

The article titled "COVID-19 triggers pulmonary tumor outgrowth through hypoxia- and inflammation-induced VEGF-dependent angiogenesis," published in Signal Transduction and Targeted Therapy, systematically explores the molecular mechanisms by which Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection induces pulmonary hypoxia and inflammation, subsequently activating the Vascular Endothelial Growth Factor (VEGF) signaling pathway, ultimately leading to the recurrence of dormant tumors within the lungs.

Background Knowledge

This study aims to address the clinical challenge of sudden increases in tumor burden in lung cancer patients following SARS-CoV-2 infection. Currently, the mechanisms governing the maintenance and disruption of tumor dormancy are not fully understood; in particular, how hypoxia and inflammation within the microenvironment synergistically trigger the angiogenic switch remains a research bottleneck. As a key pro-angiogenic factor, VEGF expression is regulated by HIF-1α. However, in the context of viral infection, direct evidence regarding how VEGF specifically drives the transformation of pulmonary nodules into malignant tumors is lacking. This study utilizes the K18-hACE2 transgenic mouse model to simulate human COVID-19 pathological features, verifying the central role of the VEGF-VEGFR2 axis in virus-induced tumor outgrowth and exploring the therapeutic potential of blocking this pathway.

 

 

Research Methods and Experiments

The authors constructed an immunocompetent K18-hACE2 mouse model, simulating severe human COVID-19 pathology through intranasal inoculation of SARS-CoV-2. The study first confirmed via histopathology, immunofluorescence, and qPCR that viral infection led to severe pulmonary hypoxia (characterized by high expression of CA9 and HIF-1α), inflammatory infiltration, and a surge in angiogenesis (with CD31+ microvessel density increasing more than 9-fold).

Subsequently, the research team established a dormant Lewis Lung Carcinoma (LLC) tumor model to observe the impact of viral infection on tumor growth. Experiments revealed that in mice infected with SARS-CoV-2, the tumor formation rate of LLC cells surged from 28% to 100%, accompanied by a significant increase in tumor volume and a dramatic upregulation of VEGF and VEGFR2 expression levels.

To verify causality, researchers constructed an LLC cell line overexpressing VEGF, confirming that high VEGF expression significantly lowered the cellular threshold required for tumor formation, mimicking the virus-induced pro-angiogenic environment. Finally, intervention experiments using a humanized anti-VEGF neutralizing antibody (Suvemcitug) successfully inhibited tumor growth and angiogenesis in virus-infected mice, restoring pulmonary hypoxic states and immune cell infiltration.

Key Conclusions and Perspectives

• SARS-CoV-2 infection causes drastic changes in the pulmonary microenvironment, including severe hypoxia, inflammation, and upregulated VEGF expression (mRNA increased by approximately 180-fold), which are key factors triggering the disruption of tumor dormancy.
• VEGF-dependent angiogenesis is a necessary condition for COVID-19-induced pulmonary tumor outgrowth; blocking the VEGF signal significantly inhibits tumor progression, a conclusion verified in both VEGF-overexpression models and antibody blockade experiments.
• HIF-1α-mediated VEGF transcriptional activation is the core molecular mechanism linking viral infection to tumor angiogenesis, and the upregulation of VEGFR2 further amplifies this signaling pathway.
• Clinical sample analysis shows that lung tissues from severe COVID-19 patients exhibit consistent VEGF overexpression, VEGFR2 upregulation, and disorganized vascular structures with the mouse model, confirming the relevance of this mechanism in human disease.

Research Significance and Prospects

This finding holds significant guidance for drug development, suggesting that the combined use of anti-VEGF drugs during COVID-19 treatment or post-recovery management may effectively prevent or control the recurrence of latent tumors. For clinical monitoring, the study emphasizes the necessity of dynamically assessing pulmonary microvessel density and VEGF levels following viral infection to early identify risks of tumor activation. Furthermore, this research provides a new paradigm for disease modeling, utilizing viral infection models to study how microenvironmental stress disrupts tumor dormancy, aiding in the development of novel anti-cancer strategies targeting hypoxic and inflammatory microenvironments.

 

 

Conclusion

From molecular mechanisms to clinical samples, this study comprehensively constructs the pathological chain of SARS-CoV-2 infection disrupting tumor dormancy via the hypoxia-VEGF-angiogenesis axis. This not only explains the increased risk of lung cancer in COVID-19 patients but also provides new therapeutic targets for early lung cancer intervention. For clinical care systems, this means that in managing sequelae of viral infections, there must be high vigilance regarding the risk of tumor activation caused by microenvironmental changes, and anti-angiogenic therapies should be considered for inclusion in comprehensive treatment plans. This study provides a solid scientific foundation for understanding the interaction between infection and tumors, with profound implications for improving the long-term prognosis of patients with pulmonary diseases.

 

Xu Jing, Mingwei Ma, Yan Bai, Yuguo Chen, and Yihai Cao. COVID-19 triggers pulmonary tumor outgrowth through hypoxia- and inflammation-induced VEGF-dependent angiogenesis. Signal Transduction and Targeted Therapy.