BREAKING COVID-19 News! Polish Review Study Shows That SARS-CoV-2 Infections Are A Potential Risk Factor For The Development Of Cancer!

COVID-19 Cancer: The COVID-19 pandemic has been an unprecedented global health crisis, with millions of cases and deaths reported worldwide. While the primary concern has been the acute respiratory effects of the SARS-CoV-2 virus, emerging research suggests that its implications might extend beyond immediate health concerns. A review study conducted by the Medical University of Silesia in Poland has delved into the potential link between SARS-CoV-2 infection and the development of cancer. This comprehensive analysis considers various factors that may connect the two, shedding light on possible mechanisms and long-term implications.


 
The Broad Clinical Spectrum of COVID-19
COVID-19 exhibits a broad clinical spectrum, ranging from asymptomatic cases to severe respiratory complications and fatalities. The virus primarily spreads through respiratory droplets via various carriers, including symptomatic, pre-symptomatic, and asymptomatic individuals, as well as contaminated surfaces. SARS-CoV-2 has also been shown to modulate the immune system and trigger low-grade chronic inflammation, potentially contributing to cancer development over the long term.
 
Cancer as a Global Health Concern
Cancer is a significant global health concern, with millions of survivors worldwide. Some data suggest that SARS-CoV-2 may act as a potential risk factor for cancer development, making it essential to investigate this connection thoroughly. The review summarizes existing data on how SARS-CoV-2 might impact cancer development by affecting various biological processes.
 
SARS-CoV-2 and Cancer Outcomes
Furthermore, the COVID-19 Cancer study highlights the implications of SARS-CoV-2 infection on cancer outcomes. The virus can influence the host's immune response, potentially altering the course of cancer treatment, especially when combined with immunotherapy. Inflammation induced by the virus can affect cancer cell behavior, including proliferation, survival, angiogenesis, and metastasis. Immune cell infiltration, driven by both cancer and SARS-CoV-2 infection, results in the secretion of inflammatory cytokines, further linking these two health challenges. Elevated levels of cancer-promoting growth factors have also been observed in patients with hematological malignancies after SARS-CoV-2 infection.
 
This review underscores the need for a comprehensive understanding of the potential interplay between SARS-CoV-2 infection and cancer development. It explores various avenues through which the virus might impact oncogenesis and cancer progression, highlighting the importance of ongoing research in this crucial area of public health concern.
 
SARS-CoV-2 and Cancer: Implications for Immunity and Immune Escape
The increased incidence or recurrence of cancer in COVID-19 patients may be attributed to compromised immune surveillance caused by SARS-CoV-2 infection. Key immune cells, such as CD8+ cytotoxic lymphocytes, are crucial in targeting cancer cells through antigen recognition. CD4+ lymphocytes also play a role by either inhibiting or stimulating cytotoxic lymphocytes in th e antitumor response. SARS-CoV-2 infection is associated with lymphopenia, reduced CD4+ and CD8+ T cell counts, and decreased natural killer (NK) cell activity, along with an overexpression of inhibitory receptor NKG2A. This leads to diminished production of essential cytokines and a functional depletion of CD8+ T and NK cells, mirroring changes seen in some cancer types with tumor growth.
 
Immune Escape and Its Complex Interplay
Immune escape (IE) is a phenomenon where cancer cells evade immune elimination mechanisms, often by losing their antigenicity or immunogenicity. The recruitment of immunosuppressive cells further shapes a conducive microenvironment for tumor progression, metastasis, and angiogenesis. Viruses can also exacerbate IE, impairing the host immune system's response to the infectious agent. Several mechanisms affecting immune surveillance have been observed in SARS-CoV-2, such as dysregulation of interferon-I (IFN-I) production, cytokine release, dysfunction of dendritic cells, macrophages, NK cells, and neutrophils. However, the precise relationship between SARS-CoV-2 and cancer immune surveillance remains a topic of ongoing investigation.
 
DAMP and PAMP Molecules: A Potential Connection Between SARS-CoV-2 Infection and Cancer Development
The connection between SARS-CoV-2 infection and oncogenesis lies in the shared patterns of antigenic stimulation involving DAMP (damage-associated molecular pattern) and PAMP (pathogen-associated molecular pattern) molecules in both cancer and infectious diseases. When the virus infects the body, the immune system recognizes it through pattern recognition receptors (PRRs) during innate immunity. These receptors identify PAMPs and DAMPs, initiating a response that includes natural killer (NK) cells releasing cytotoxic granules, cytokine production, and apoptosis of infected cells. This process also leads to inflammation, oxidative stress, and tissue damage.
 
Hypoxia and the Tumor Microenvironment
The hypoxic microenvironment created by inflammation can trigger oxidative stress and potentially contribute to malignant transformation. Additionally, hypoxia induces the synthesis of lysyl oxidase (LOX), which promotes cancer cell invasion and migration. Various cellular processes associated with cancer initiation, progression, and metastasis occur within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) stimulate cancer cell growth by releasing growth factors while inhibiting immune responses, including NK and T-cell activity. Hypoxia within the TME exacerbates this by causing fibrosis, reducing blood supply, and promoting immune-inhibitory molecules.
 
Interestingly, SARS-CoV-2 enters cells through ACE receptors, which impact the renin-angiotensin-aldosterone system (RAAS). Elements of RAAS are expressed in TME components, including CAFs. Macrophages are also a significant part of the TME, and their phenotype shifts from M1 to M2 due to hypoxia, affecting tumor growth dynamics. Similarly, during SARS-CoV-2 infection, there's a transition from a pro-inflammatory state to immunosuppression and M2 macrophage
polarization.
 
Hypoxia, Cancer-Associated Adipocytes, and Viral Infections
Hypoxia plays a crucial role in modulating both tumor immunity and the immune response during SARS-CoV-2 infection. Tumor-associated macrophages (TAMs) shift towards an M2-like state in hypoxic conditions, actively engaging in immunosuppression and angiogenesis. Similar patterns of immune response are observed in COVID-19, shifting from inflammation to compensatory immunosuppression and M2 macrophage polarization.
 
Moreover, cancer-associated adipocytes (CAA) are an essential component of the TME. They interact with cancer cells through cytokine exchange, influencing cancer cell behavior and invasiveness. The release of free fatty acids (FFA) from adipocytes can serve as an energy source for cancer cells. The bidirectional interaction between tumor cells and CAA contributes to cancer invasion and resistance to oncolytic virus therapy.
 
Additionally, EBV infection has been suggested to alter gene expression in adipocytes, affecting their functionality and the TME. These complex interactions between immune responses, tumor microenvironment components, and viral infections highlight potential links between SARS-CoV-2 infection and oncogenesis, which warrant further investigation.
 
SARS-CoV-2: Cytokine Storm and Oxidative Stress
SARS-CoV-2 infection can trigger a dangerous condition known as a cytokine storm, characterized by excessive immune response and elevated levels of circulating cytokines, including IL-1β, IL-6, IP-10, TNF-alpha, IFN-γ, MIP-1α, MIP-1β, and VEGF. Elevated IL-6 levels, in particular, are linked to COVID-19 severity and are associated with inflammation, oncogenesis, and cytokine storms. IL-6 primarily acts through the STAT3 pathway, impacting survival, cell proliferation, angiogenesis, and tumor development, suggesting a role in cancer.
 
TNF-alpha levels are also higher in severe COVID-19 cases and are involved in chronic inflammation, apoptosis, angiogenesis, and immunity. TNF-alpha's role in cancer is complex, inhibiting cancer development through TNFR1 while promoting it through TNFR2, and altering the microenvironment to enhance tumor invasiveness and metastasis. Chemokines like CCL2, CCL4, CXCL8, CXCL9, and CXCL10, which are elevated in COVID-19, can contribute to oncogenesis by promoting tumor cell growth, cancer stem cell proliferation, metastasis, angiogenesis, and immune cell recruitment.
 
Additionally, SARS-CoV-2 infection leads to a decrease in ACE2 receptors on cell surfaces, increasing pro-inflammatory and oxidative effects of angiotensin II, resulting in oxidative stress. Reactive oxygen species (ROS) production, associated with macrophage activity in acute COVID-19 and mechanical ventilation, can contribute to cancer development by causing oxidative damage to cellular molecules, impairing DNA repair mechanisms, and altering gene expression patterns. These interconnected factors highlight the potential links between SARS-CoV-2 infection, cytokine storms, oxidative stress, and cancer development, necessitating further research.
 
Potential Links Between SARS-CoV-2 and Oncogenesis
 
-SARS-CoV-2 Genome Integration and Cancer Induction
 
Viral Genome Integration Mechanism: Certain viruses like HBV, HCV, EBV, and HPV are known to integrate their genetic material into the host genome, promoting oncogenesis. This phenomenon involves the insertion of viral DNA or RNA into the host DNA, inducing mutagenesis and leading to the transformation of host cells.
 
Epigenetic Changes: Oncoviruses, including SARS-CoV-2, trigger epigenetic changes in host cells. These changes involve DNA methylation, histone modification, chromatin remodeling, and the production of virus-encoded non-coding RNAs. These modifications alter gene expression, contributing to cancer development.
 
SARS-CoV-2 Integration Hypotheses: There are hypotheses suggesting that SARS-CoV-2 may integrate into the human genome. Evidence includes prolonged RNA detection and "re-positive" cases post-COVID-19 recovery. SARS-CoV-2 is an RNA virus that can potentially integrate into host DNA via mechanisms involving LINE-1 retrotransposition. However, such integration appears rare.
 
Stimulating Signaling in Oncogenic Pathways
IL-6/JAK/STAT Signaling Pathway: SARS-CoV-2 activates signaling pathways, including JAK/STAT, NFκB, and IFN-I. IL-6, produced during infection, plays a role in oncogenesis, promoting cell growth, invasiveness, metastasis, and immune suppression. IL-6/JAK/STAT3 signaling is implicated in multiple cancers and poor clinical prognosis.
 
Nuclear Factor κB Pathway: Hyperactivation of the NFκB pathway, seen in severe SARS-CoV-2 cases, contributes to inflammation. This pathway also plays a role in cancer progression, making it a target for cancer treatment.
 
Type I Interferon (IFN-I) Signaling: IFN-I signaling normally inhibits tumorigenesis, but SARS-CoV-2 can suppress this response. Dysregulated IFN-I signaling may impair the anti-tumor immune response.
Cell Cycle Dysregulation
SARS-CoV-2's Main Oncogenic Effect: SARS-CoV-2 may induce oncogenesis primarily through cell cycle dysregulation. Viral proteins Nsp3 and Nsp15 can degrade tumor suppressor proteins, P53 and Rb. The virus also interacts with other tumor-related proteins, promoting cell proliferation.
 
Epigenetic Changes and Genetic Mutations
Epigenetic Modifications: SARS-CoV-2 infection induces epigenetic changes, including DNA methylation, histone modification, and interactions with non-coding RNAs. These changes can lead to dysfunctional immune responses and contribute to carcinogenesis.
 
Oncolytic Effects of SARS-CoV-2
Viral Killing of Cancer Cells: Some studies suggest that SARS-CoV-2 may have oncolytic effects, directly killing cancer cells. Pro-inflammatory cytokines released during infection can enhance immune responses against infected cancer cells.
 
Reactivation of Dormant Cancer Cells (DCC)
SARS-CoV-2 and DCC Activation: SARS-CoV-2 infection can activate dormant cancer cells. Neutrophil-derived structures called extracellular neutrophil traps (NETs) may promote the proliferation and metastasis of cancer cells.
 
Disruption of the Tumorigenic Environment, Immune Inhibition, Surveillance, and Immunosuppression
 
SARS-CoV-2's Impact on the Tumor Microenvironment: SARS-CoV-2 infection can create a tumor-friendly environment with chronic inflammation and immune suppression. Immune exhaustion and the NLRP3 inflammasome activation can promote tumor growth.
 
Potential Impact of Antiviral Therapy on Cancer
Antiviral Drugs and Cancer Risk: Some antiviral drugs used to treat COVID-19 may increase the risk of cancer. Conversely, SARS-CoV-2 infection itself may induce an anti-tumor response in some cases.
 
Long-COVID and Potential Long-term Effects
Long-COVID and Immune Alterations: Long-COVID can lead to persistent immune alterations, impacting T-cell responses and promoting low-grade chronic inflammation. This may influence cancer development and progression.
 
Conclusion
SARS-CoV-2's Complex Relationship with Oncogenesis: SARS-CoV-2 exhibits multifaceted interactions with oncogenic pathways and the immune system. It poses challenges and potential risks related to cancer development and progression. Further research is needed to clarify these relationships and inform clinical practice.
 
The study findings were published in the peer reviewed journal: Frontiers in Molecular Sciences.
https://www.frontiersin.org/articles/10.3389/fmolb.2023.1260776/full
 
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