COVID-19 has emerged as the greatest public health challenge of our time, affecting millions of lives worldwide. While treatments such as antiviral agents, neutralizing antibody therapy, and hormonotherapy have been explored, a specific medicine for treating COVID-19 is still not available.
On the other hand, malignant tumors, including bladder cancer, continue to pose significant clinical challenges and contribute to the global burden of life-threatening diseases.
Bladder cancer stands out as one of the leading causes of tumor-induced deaths across the globe . Despite variations in individual patient responses and the development of drug tolerance, immunotherapy remains a potent clinical treatment strategy for bladder cancer patients.
In the context of medical diagnosis, patients with bladder cancer, particularly those in advanced stages, often exhibit alterations in immune cell components, especially after extended chemotherapy. These immune dysregulations can potentially contribute to tumorigenicity, including the development of bladder cancer .
Moreover, it has been reported that cancer patients, including those with bladder cancer, are at a higher risk of severe COVID-19 outcomes due to the interplay between tumor therapy-induced immune system alterations and the chronic comorbidities triggered by COVID-19 infection.
This places bladder cancer patients in a vulnerable position during the ongoing pandemic, potentially affecting their clinical treatment efficacy and overall survival duration.
In this comprehensive study, we set out to explore the intersection of bladder cancer and COVID-19, with a particular focus on identifying potential therapeutic targets and novel approaches to treatment. We conducted an extensive analysis that included the identification of differentially expressed genes (DEGs) in bladder cancer, the discovery of intersecting genes between bladder cancer and COVID-19, and the development of a risk score comprising 21 risk factors correlated with clinical phenotypes and gene expression characteristics in bladder cancer patients.
Results and Findings
Our analysis yielded several noteworthy findings. Firstly, we identified 1150 DEGs in bladder cancer, and among these, 189 genes were found to intersect with COVID-19. The risk score we developed demonstrated a strong correlation with clinical phenotypes, with higher risk scores being associated with increased death rates/risk in bladder cancer patients. This suggests that the risk score may serve as an indicator of therapeutic efficiency in bladder cancer cases.
Furthermore, our analysis revealed that the 21 target gene expressions significantly associated with the overall survival of bladder cancer patients could potentially serve as diagnostic hallmarks for both bladder cancer and COVID-19.
The dimensionality reduction analysis demonstrated distinct gene expression profiles between high-risk and low-risk groups of bladder cancer patients, further emphasizing the relevance of the risk score in predicting patient outcomes.
To gain a deeper understanding of the potential pharmacological targets in bladder cancer and COVID-19, we conducted network pharmacology analysis. This analysis identified 10 core targets for pachymic acid, a promising bioactive ingredient. These targets were associated with functional enrichment related to microenvironmental regulation, reduction of cell proliferation, regulation of molecular immunology, and inhibition of viral activity.
Molecular docking analysis provided insights into the key targeting proteins, including CCL2, THBS1, and MMP1. These proteins have been implicated in various aspects of oncogenesis, tumor microenvironment modulation, and inflammation.
CCL2, for instance, plays a crucial role in creating an immunosuppressive microenvironment, promoting tumor angiogenesis, and may also serve as a prognostic factor for severe COVID-19.
CCL2: A Chemokine with Multiple Roles in Disease
CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a small protein that belongs to the chemokine family. Chemokines are molecules that attract and activate immune cells. CCL2 is particularly important for recruiting monocytes, a type of white blood cell that plays a role in inflammation and immunity.
CCL2 is produced by a variety of cells, including tumor cells, immune cells, and endothelial cells (cells that line blood vessels). CCL2 can act on its target cells through a receptor called CCR2. When CCL2 binds to CCR2, it triggers a series of events that lead to the recruitment of monocytes to the area.
In the tumor microenvironment, CCL2 plays a role in creating an immunosuppressive environment. This is because CCL2 can attract and activate immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. These cells can suppress the immune response to tumor cells, making it more difficult for the body to fight cancer.
CCL2 can also promote tumor angiogenesis, the growth of new blood vessels in tumors. This is because CCL2 can attract and activate endothelial cells, which are the cells that line blood vessels. When new blood vessels grow into tumors, they provide the tumors with the nutrients and oxygen they need to grow and spread.
In addition to its role in cancer, CCL2 has also been implicated in other diseases, including rheumatoid arthritis, psoriasis, and asthma. CCL2 levels are often elevated in these diseases, and there is evidence that CCL2 can contribute to their development and progression.
CCL2 may also play a role in COVID-19. Studies have shown that CCL2 levels are elevated in the blood of patients with severe COVID-19. Additionally, CCL2 can attract and activate immune cells that can contribute to the development of lung inflammation and damage.
Overall, CCL2 is a chemokine with multiple roles in disease. It is involved in the development and progression of cancer, as well as other diseases such as rheumatoid arthritis, psoriasis, and asthma. CCL2 may also play a role in COVID-19. More research is needed to fully understand the role of CCL2 in these diseases and to develop strategies to target CCL2 for therapeutic purposes.
Here are some additional details on the role of CCL2 in immunosuppression, tumor angiogenesis, and COVID-19:
- Immunosuppression: CCL2 can attract and activate immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. These cells can suppress the immune response to tumor cells, making it more difficult for the body to fight cancer. CCL2 can also suppress the immune response to other diseases, such as rheumatoid arthritis and psoriasis.
- Tumor angiogenesis: CCL2 can promote tumor angiogenesis by attracting and activating endothelial cells. Endothelial cells are the cells that line blood vessels. When new blood vessels grow into tumors, they provide the tumors with the nutrients and oxygen they need to grow and spread.
- COVID-19: Studies have shown that CCL2 levels are elevated in the blood of patients with severe COVID-19. Additionally, CCL2 can attract and activate immune cells that can contribute to the development of lung inflammation and damage. CCL2 may also play a role in the development of other complications of COVID-19, such as acute respiratory distress syndrome (ARDS).
The research on the role of CCL2 in disease is still ongoing. However, the evidence to date suggests that CCL2 is a key player in a number of diseases, including cancer, COVID-19, and autoimmune diseases. More research is needed to fully understand the role of CCL2 in these diseases and to develop strategies to target CCL2 for therapeutic purposes.
THBS1, on the other hand, influences angiogenesis, antitumor immunity, and cell migration . MMP1 has been associated with oncogenesis and metastasis in common cancers and elevated levels in COVID-19 patients.
Pachymic acid has demonstrated anti-cancer activities through the regulation of endoplasmic reticulum stress and mitochondrial dysfunction, as well as in vivo and in vitro preclinical studies.
This suggests that pachymic acid may enhance the therapeutic effectiveness of antivirals and immunotherapy for bladder cancer and COVID-19 in future clinical practice.
Limitations and Future Directions
While our study provides valuable insights, certain limitations must be acknowledged. The risk assessment score was established retrospectively, and further clinical verification is essential to validate its predictive utility. Additionally, the pharmacological biotargets identified through network pharmacology and molecular docking analyses require experimental validation before clinical application can be considered.
In conclusion, our comprehensive analysis has shed light on the therapeutic prognosis and clinical phenotype of bladder cancer patients, with a particular emphasis on the intersection with COVID-19. Pachymic acid has emerged as a promising bioactive ingredient with potential anti-bladder cancer/COVID-19 actions.
The pharmacological mechanisms underlying these effects encompass anti-cancer and anti-inflammatory pathways, as well as immunomodulation. Moreover, pachymic acid may exert its antiviral effects by effectively binding to core target proteins in COVID-19.
Despite the limitations of this study, our findings open up new avenues for research and therapeutic development. The intersection of bladder cancer, COVID-19, and pachymic acid presents a unique opportunity to enhance the treatment options available to patients facing these challenging conditions.
Future clinical trials and experimental studies are warranted to further explore the potential of pachymic acid and the identified biotargets in improving the lives of bladder cancer patients, particularly in the context of the ongoing COVID-19 pandemic.
reference link : https://www.tandfonline.com/doi/full/10.1080/10942912.2023.2252194