In December 2019, an outbreak of atypical viral pneumonia occurred in Wuhan, People’s Republic of China, later identified as being caused by a new coronavirus. The disease spread rapidly, resulting in significant global morbidity and mortality, ultimately being named COVID-19, caused by the SARS-CoV-2 virus. This novel virus is part of the beta-coronavirus family, which includes previous pandemic-causing viruses like SARS-CoV in 2002 and MERS-CoV in 2012. Though coronaviruses were not initially considered significant pathogens before these outbreaks, their ability to cause severe respiratory syndromes brought attention to their virulence and the broader implications of coronavirus infections.
COVID-19’s spread, along with its high admission rates to intensive care units and associated mortality, especially due to severe respiratory failure, prompted widespread concern and led to unprecedented global public health responses. The impact of COVID-19 extends far beyond acute respiratory distress; long-term effects, particularly regarding carcinogenesis, are becoming a point of focus in scientific investigations. Carcinogenesis, or the process of cancer formation, is influenced by a combination of genetic mutations, epigenetic alterations, and environmental factors, and recent studies are exploring how SARS-CoV-2 might contribute to or exacerbate this process.
COVID-19 triggers a profound immune response, often involving a “cytokine storm,” which can lead to sustained inflammation, DNA damage, and subsequent cellular abnormalities. Prolonged inflammatory states have long been associated with increased cancer risk, and the chronic inflammation observed in COVID-19 survivors could create conditions favorable to cancer development. Markers of oxidative stress and persistent immune dysregulation found in COVID-19 patients months after recovery add to concerns that the virus may have a long-term impact on cancer incidence.
| Category | Detail | Mechanisms | Relevant Pathologies |
|---|---|---|---|
| Virus & Protein Interactions | SARS-CoV-2 Spike Protein (S) | – The spike protein facilitates viral entry into host cells by binding to ACE2 receptors. Activation requires cleavage by host proteases (FURIN, TMPRSS2). Two Cleavage Sites: S1/S2: Exposes the receptor-binding domain. S2′: Triggers fusion with the host cell membrane. TMPRSS2 & FURIN are involved in activating viral entry and potentially cancer metastasis. | COVID-19 (severe cases), Prostate Cancer, Colorectal Cancer (linked to KRAS, BRAF mutations), Lung Cancer (due to TMPRSS2 overexpression) |
| Immune Response | Cytokine Storm | – Overproduction of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β. Associated with severe COVID-19 cases and linked to chronic inflammation in survivors. Pro-inflammatory cytokines drive immune dysregulation, oxidative stress, and DNA damage. Key Inflammatory Markers: IL-6, TNF-α, Ferritin, C-reactive protein. | COVID-19 (acute and chronic cases), Pulmonary Fibrosis, Increased Cancer Risk (due to persistent inflammation), Leukemias and Lymphomas (immune dysregulation) |
| ACE2 Receptor & RAAS Pathway | ACE2 Receptor | – ACE2 converts AGTII into angiotensin (1-7), mitigating AGTII’s pro-inflammatory effects. SARS-CoV-2 downregulates ACE2 by binding to it, leading to AGTII accumulation. AGTII promotes cellular proliferation, angiogenesis, and inflammation. Loss of ACE2 exacerbates pro-inflammatory pathways, contributing to cancer risk. | Lung Injury, Chronic Inflammation, Increased Cancer Risk (via proangiogenic AGTII activity), Worsening of Pre-existing Conditions |
| Genetic & Epigenetic Alterations | DNA Methylation, Histone Modification | – SARS-CoV-2 alters DNA methylation patterns, especially hypermethylation of tumor suppressor genes. Modulates histone modifications, impacting oncogenes and tumor suppressor gene expression. Epigenetic changes can lead to malignant transformation by silencing tumor suppressor genes and activating oncogenes. | Increased Risk of Cancer Development, Long-term Genetic and Epigenetic Damage, Potential Role in Post-COVID Carcinogenesis |
| Protease Activity | FURIN & TMPRSS2 Proteases | – FURIN and TMPRSS2 are crucial for the activation of viral spike proteins, facilitating SARS-CoV-2 entry into host cells. FURIN: Associated with cancer cell proliferation, migration, and invasion, involved in several cancers (lung, head and neck, colon). TMPRSS2: A key player in prostate cancer progression and viral propagation. | Prostate Cancer, Lung Cancer, Colorectal Cancer, Lung Fibrosis |
| COVID-19 Therapeutics & Risks | Corticosteroids, Immunosuppressants | – Corticosteroids and immunosuppressive drugs are used to manage severe COVID-19 but may impair immune surveillance over time. Long-term immunosuppression can increase susceptibility to oncogenic viral infections (e.g., EBV, HPV). Suppression of immune system leads to reduced ability to eliminate pre-cancerous cells. | Risk of Cancer, Increased Susceptibility to Oncogenic Viral Infections (EBV, HPV), Weakened Immune Response to Cancer Cells |
| Co-infections | EBV, HPV, and Other Viral Co-infections | – Co-infection with oncogenic viruses (EBV, HPV) may worsen COVID-19 outcomes. EBV reactivations due to immune suppression from COVID-19. Oncogenic potential amplified in co-infected patients due to compounded immune dysregulation and chronic inflammation. | EBV-induced Cancers (Lymphomas), HPV-related Cancers (Cervical, Oropharyngeal), Increased Risk of Viral-induced Carcinogenesis |
| Cancer Behavior Post-COVID-19 | Changes in Tumor Characteristics | – Emerging evidence suggests COVID-19 may influence tumor aggressiveness and behavior. Higher proliferation rates and increased incidence of aggressive cancer subtypes (e.g., triple-negative breast cancer). Chronic inflammation and immune dysregulation post-COVID could drive more aggressive cancer phenotypes. | Breast Cancer, Triple-Negative Breast Cancer, Synchronous/Metachronous Primary Cancers |
| Rare Cell-type Cancers | Small Cell Carcinoma, Angiosarcoma | – Evidence suggests a rise in rare cancers like small cell carcinoma and angiosarcoma post-COVID. Immune dysregulation and chronic inflammation post-COVID may promote the development of rare cancer types. Prolonged immune suppression and inflammatory state may contribute. | Small Cell Carcinoma, Angiosarcoma, Rare Aggressive Cancers Post-COVID |
The intersection of COVID-19 and cancer risk is also influenced by the virus’s molecular and cellular effects. Specifically, COVID-19 infection reduces levels of angiotensin-converting enzyme 2 (ACE2) in the body, triggering an inflammatory cascade involving angiotensin II (AGTII) and subsequent immune dysregulation. ACE2 plays a key role in regulating blood pressure and inflammation, and its reduction during COVID-19 could lead to chronic inflammatory states that promote carcinogenesis. Furthermore, the viral spike protein, critical for the virus’s entry into cells, engages host cell proteases like TMPRSS2 and FURIN, which are also implicated in cancer progression. These proteases are involved in the cleavage of viral proteins necessary for infection, but they also play roles in normal cellular processes, including tissue repair and immune response modulation. Altered activity of these proteases in the context of COVID-19 may inadvertently promote oncogenic pathways.
One area of significant concern is the potential for SARS-CoV-2 to induce genetic and epigenetic changes that could lead to cancer. DNA methylation patterns, histone modifications, and other epigenetic mechanisms that regulate gene expression can be altered by viral infections, including COVID-19. Such changes can silence tumor suppressor genes or activate oncogenes, thereby setting the stage for cancer development. For instance, the hypermethylation of tumor suppressor genes is a well-known mechanism through which viruses can contribute to cancer, and similar patterns have been observed in COVID-19 patients.
Moreover, long-term immune dysregulation caused by COVID-19 may exacerbate pre-existing conditions, including cancer. Studies have found that cancer patients who contract COVID-19 are more likely to experience cancer progression, possibly due to the virus’s effects on the immune system. The elevated levels of cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in severe COVID-19 cases have been linked to worse outcomes in cancer patients, underscoring the complex relationship between the virus, the immune system, and cancer.
Table : describes the features of post-COVID-19 cancer development.
| Cancer Development Feature | Details | Key Findings |
| Increased cancer risk | COVID-19 survivors show an increased risk of cancer development, particularly due to immune dysregulation and chronic inflammation. | Increased IL-6 and TNF-α levels, oxidative stress markers, prolonged inflammation |
| Epigenetic alterations | Alterations in DNA methylation patterns, particularly hypermethylation of tumor suppressor genes, contributing to malignant transformation. | Hyperactive oncogenic pathways (e.g. JAK-STAT, MAPK, NF-κB) identified in post-COVID cases |
| Synchronous and metachronous cancers | Post-COVID-19, there is an increased occurrence of synchronous and metachronous primary cancers, possibly due to immune suppression and chronic inflammation. | Studies show higher incidence of multiple primary tumors and hematological malignancies such as lymphoma and leukemia |
| Rare cell type cancers | Increased incidence of rare cancers such as small cell carcinoma and angiosarcoma, potentially linked to COVID-19-induced immune dysregulation. | Significant rise in rare cell type cancers documented in post-COVID-19 cases |
IL-6: interleukin-6; TNF-α: tumor necrosis factor alpha; JAK-STAT: Janus kinase/signal transducers and activators of transcription; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells
Research also indicates that certain COVID-19 therapeutics, particularly corticosteroids and immunosuppressive drugs, may have unintended long-term consequences, including increased cancer risk. These drugs, while essential in managing severe COVID-19 symptoms, can impair immune surveillance, allowing for the unchecked proliferation of pre-cancerous cells. The balance between managing acute COVID-19 symptoms and mitigating long-term carcinogenic risks remains a critical challenge for healthcare providers.
Co-infections with other oncogenic viruses, such as Epstein-Barr virus (EBV) and human papillomavirus (HPV), further complicate the cancer landscape in COVID-19 patients. These co-infections can lead to more severe disease outcomes and may synergize with COVID-19 to enhance cancer risk. The immune modulation caused by multiple infections can overwhelm the body’s natural defenses against cancer, creating a more favorable environment for tumor growth.
Synchronous and metachronous second primary cancers are another concern in the post-COVID-19 era. Synchronous cancers, which are two or more primary cancers diagnosed simultaneously or within a short period, may become more common as the immune system is compromised by COVID-19. Studies have suggested that the persistent inflammation seen in “long COVID” survivors could create conditions favorable to the development of multiple primary tumors, especially in the context of immune suppression and chronic inflammation.
Interestingly, changes in cancer behavior post-COVID-19 have also been documented. Some studies report that cancers diagnosed after COVID-19 appear more aggressive, with higher proliferation rates and worse prognoses than those diagnosed pre-pandemic. For example, breast cancer patients diagnosed after COVID-19 are more likely to have triple-negative breast cancer, a subtype that is more difficult to treat and has a poorer outlook.
Additionally, the incidence of rare cell-type cancers, such as small cell carcinoma and angiosarcoma, has risen in the post-COVID-19 period. These rare cancers may be linked to COVID-19-induced immune dysregulation and chronic inflammation, though the mechanisms behind this increase are not yet fully understood.
Ongoing research is crucial to fully understand the long-term cancer risks associated with COVID-19. Longitudinal studies tracking cancer incidence in COVID-19 survivors, as well as investigations into the molecular mechanisms by which SARS-CoV-2 influences gene expression, are needed to clarify the virus’s role in carcinogenesis. Furthermore, the safety of COVID-19 therapeutics must be continuously evaluated to ensure that their benefits outweigh any potential long-term risks, including cancer development.
In conclusion, while the acute effects of COVID-19 on the respiratory system have been well-documented, its long-term impact on cancer risk remains a critical area of investigation. The complex interplay between immune dysregulation, chronic inflammation, and epigenetic changes in COVID-19 patients suggests that the pandemic may have far-reaching implications for cancer incidence in the coming years. Understanding these mechanisms is vital for developing strategies to mitigate the potential increase in cancer cases as a consequence of the COVID-19 pandemic.
reference : https://www.cureus.com/articles/289494-covid-19-and-carcinogenesis-exploring-the-hidden-links#!/
