SARS-COV-2 Virus and Cancer: Unraveling the Complex Interplay

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Cancer continues to be a global threat, claiming over 10 million lives each year [1]. Despite advancements in cancer therapies that have improved survival rates, the debilitating side effects of these treatments limit the options available for patients [2].

Early and accurate diagnosis, followed by a precise characterization of the cancer type, are critical for effectively managing cancer patients and increasing their chances of survival. Late diagnosis after emergency presentation is associated with poor prognosis [3,4,5].

Cancer is a complex and devastating disease that arises from the uncontrolled growth and proliferation of cells, leading to the formation of tumors. While many factors can contribute to cancer development, one intriguing aspect is the involvement of oncogenic viruses, which have the ability to promote tumorigenesis in infected cells.

In this article, we will explore the mechanisms through which seven well-known oncoviruses contribute to cancer formation, namely human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), Epstein-Barr virus (EBV), human T-cell leukemia virus 1 (HTLV-1), Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), and Merkel cell polyomavirus (MCPyV)

Oncoviruses: Agents of Cellular Hijacking

Oncogenic viruses are characterized by their ability to manipulate host cellular pathways to promote their own propagation and survival. These viruses have relatively small genomes ranging from a few kilobases to around 200 kilobases, which limit their coding capacity.

As a result, they rely heavily on the host cell’s proteome to hijack cellular pathways, enabling them to take control of the host cell’s machinery. This intricate process involves several steps, from the in situ formation of the tumor to the generation of circulating metastatic cells, all of which rely on the differential regulation of proliferation, apoptosis, and senescence pathways.

The Seven Oncogenic Viruses and Their Mechanisms

  • Human Papillomavirus (HPV): HPV is one of the most well-known oncoviruses and is primarily associated with cervical cancer. The virus encodes viral oncoproteins E6 and E7, which interact with key tumor suppressor proteins p53 and pRB, respectively, leading to their degradation and inactivation. This disruption of the cell cycle and apoptotic pathways allows infected cells to evade normal regulatory mechanisms and persistently proliferate, leading to the development of cervical and other anogenital cancers.
  • Hepatitis B and C Viruses (HBV, HCV): Chronic infection with HBV or HCV can lead to the development of hepatocellular carcinoma (HCC). Both viruses induce chronic inflammation in the liver, which creates a microenvironment conducive to tumor development. Additionally, HBV can integrate its DNA into the host genome, potentially leading to insertional mutagenesis and activation of host oncogenes.
  • Epstein-Barr Virus (EBV): EBV is associated with several malignancies, including Burkitt’s lymphoma, nasopharyngeal carcinoma, and Hodgkin’s lymphoma. The virus expresses latent proteins that can mimic host cell signaling pathways, leading to uncontrolled cell proliferation. Moreover, EBV can also activate cellular genes involved in cell cycle progression and anti-apoptotic pathways.
  • Human T-cell Leukemia Virus 1 (HTLV-1): HTLV-1 is linked to adult T-cell leukemia/lymphoma (ATLL). The virus encodes Tax, a potent viral oncoprotein that can activate various signaling pathways, including NF-κB and CREB, leading to enhanced cell proliferation and inhibition of apoptosis.
  • Kaposi Sarcoma-Associated Herpesvirus (KSHV) or Human Herpesvirus-8 (HHV-8): KSHV is responsible for Kaposi sarcoma, a cancer frequently observed in immunocompromised individuals, such as those with HIV. KSHV expresses viral proteins that can modulate cell signaling pathways, leading to uncontrolled cell growth and survival.
  • Merkel Cell Polyomavirus (MCPyV): MCPyV is implicated in the development of Merkel cell carcinoma. The virus expresses a viral oncoprotein, Large T antigen, which can inactivate p53 and pRB tumor suppressor proteins, leading to cell cycle dysregulation and increased cell proliferation.
  • Human Immunodeficiency Virus 1 (HIV-1): While not a direct oncovirus, HIV-1 can indirectly promote cancer development. The virus causes immunosuppression, weakening the immune system’s ability to control viral infections and the growth of cancer cells. This weakened immune surveillance can increase the risk of certain cancers in HIV-infected individuals.

Direct and Indirect Oncogenic Mechanisms

Oncogenic viruses can induce cancer through direct or indirect mechanisms. Direct oncogenesis involves the integration of viral oncogenes into the host cell’s genome or the activation of existing host proto-oncogenes.

This process disrupts normal cellular regulatory mechanisms and leads to uncontrolled cell proliferation. Indirect oncogenesis, on the other hand, is associated with chronic inflammation occurring over prolonged periods of infection, leading to genomic instability and the eventual development of tumors.

Understanding the Viral Cancer Hallmarks

The discovery of the interconnections between viruses and cancer has been a significant breakthrough in virology and oncology [6]. Viruses with oncogenic potential have attracted considerable attention from the scientific community. It has been established that these viruses are necessary but not sufficient for tumor genesis; their incidence is lower than their prevalence in the human population [8].

Virus-induced cancers often emerge alongside persistent infections, even years after the acute infection. Additionally, the immune system plays a crucial role in modulating the development of viral cancers, where immunosuppression or chronic inflammation can either inhibit or promote tumor growth [8].

The Complex Mechanisms of Viral Oncogenesis

The major challenge in viral oncology is understanding the intricate pathways and mechanisms behind viral oncogenesis, involving multiple viral oncogenes and factors that promote cellular transformation. Some mechanisms can be well-characterized in specific tumors or tissues, but others are more complex, making it challenging to associate cancer with a particular causal agent or a single cellular event.

Oncogenic mechanisms can act on various spots of the host cell signaling machinery, revealing novel interconnections between processes like autophagy and mitochondrial metabolism in cancer cells [20]. This underscores the need to dissect the molecular effects of individual oncoviral events and understand how multiple or cumulative oncogenic events can influence cancer onset and progression [14].

Historical Perspective on Oncogenic Viruses

Pioneering studies in the early twentieth century identified several oncoviruses capable of inducing tumoral transformation in animals [21,22]. Later, researchers discovered that many of the viral oncogenes were actually genes of the host organism acquired through viral recombination. These oncogenes displayed their potential to induce tumoral transformation in virus-infected cells by accumulating gain-of-function mutations that altered gene expression or expressed molecules inhibiting the p53 and Rb oncosuppressors [25].

However, it is now known that classical viral oncogenes are insufficient for cancer development, and most virus-induced tumors remain benign infections [26]. Understanding the biochemical pathways perturbed by viral disease and their association with human cancers is a complex task.

The Oncogenic Potential of SARS-CoV-2

The coronavirus disease 19 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had far-reaching consequences globally, posing significant challenges to public health and economies due to its high transmission rates and pathogenicity.

The initial lack of effective treatments and vaccines further exacerbated the impact of the virus, leading to an urgent need for research and development in the medical and scientific communities [57,58,59,60,61,62,63,64].

Amidst the efforts to combat the pandemic, researchers have also explored the effects of SARS-CoV-2 infection on cancer patients. Studies have shown that individuals with pre-existing solid cancers or hematologic malignancies are more susceptible to SARS-CoV-2 infection, leading to increased morbidity and mortality rates when compared to the general population [68].

Hematological cancers, in particular, present an added challenge due to dysfunctional immune cells linked to hematopoietic malignancies that can significantly compromise the immune defenses of the affected individuals [69].

The metabolic perturbances caused by SARS-CoV-2 infection have been implicated in the systemic alterations seen in severe COVID-19 cases. Metabolic reprogramming has emerged as a distinctive feature of SARS-CoV-2, driven by the virus’s replication for survival and modulated by the host immune response [70,71,72,73].

Omics technologies have revealed reprogrammed metabolic pathways in hospitalized COVID-19 patients, affecting amino acid and lipid metabolism, carbohydrate and energy metabolism, and immune-related processes [75,76,77,78,79]. These modifications play a crucial role in the virus’s survival within the host.

Moreover, researchers have identified major signaling pathways that interact between SARS-CoV-2 and cancer cells, potentially influencing tumor progression or altering the tumor’s response to therapy. However, the causal relationship between SARS-CoV-2 and cancer remains an open question, given the observed reactivation of oncogenic viruses following COVID-19 in some cases and the paradoxical response of certain tumors to the immune modulation induced by the infection in others [80].

Similar to oncoviruses, SARS-CoV-2 may promote cancer progression by altering central metabolic pathways in both tumor cells and patients, such as carbon and nitrogen metabolism and nucleic acid metabolism [75,81]. Experimental evidence indicates that SARS-CoV-2 infection negatively regulates the expression of cholesterol-related proteins and positively regulates carbohydrate metabolism-related proteins in human biofluids and infected cells [27,75,81].

This metabolic switch may provide tumor cells with high-energy production pathways, like glycolysis, to support the virus’s replication rate [82,83].

The debate regarding the oncogenic potential of SARS-CoV-2 revolves around its impact on genes involved in oncogenesis. Studies have revealed the regulation of genes associated with E2F transcription factors and pRB upon SARS-CoV-2 infection, suggesting a potential mechanism for the virus to contribute to oncogenesis by inhibiting oncosuppressors [84].

Interactomics studies have provided valuable mechanistic insights, showing the interaction between the SARS-CoV-2 endoribonuclease non-structural protein 15 (Nsp15) and pRB, leading to the nuclear export and ubiquitination of pRB for degradation via the proteasome [86]. Cells expressing the Nsp15 protein displayed an amplified proliferative potential and loss of contact inhibition, indicating a potential role in cellular transformation [86].

Another potential oncogenic mechanism involves the degradation of the tumor suppressor protein p53, mediated by the SARS-CoV-2 non-structural protein 3 (Nsp3). The papain-like protease (PLpro) domain of Nsp3 interacts with and stabilizes the E3 ubiquitin ligase RCHY1, promoting the RCHY1-mediated degradation of p53 [87,88,89].

Considering the high sequence similarity between Nsp3 in SARS-CoV-1 and SARS-CoV-2, it is plausible that SARS-CoV-2 Nsp3 may also play a role in lowering p53 levels and increasing the probability of cellular transformation [6]. Additionally, SARS-CoV-2 may control p53 degradation by hijacking the protein through viral antigens, further suggesting the virus’s potential oncogenic role [91,92].

The modulation of macro-autophagy/autophagy by SARS-CoV-2 also raises questions about its potential impact on cancer development. Coronaviruses, including SARS-CoV-2, have been found to regulate the autophagic machinery, particularly ER-phagy, which is crucial for viral replication [93,94].

As autophagy plays a multifaceted role in cancer progression, the modulation of this process by SARS-CoV-2 could potentially promote tumorigenesis [96,97]. Moreover, elevated levels of mucin (MUC) proteins observed during COVID-19 infection in patients have raised concerns about their possible connection to cancer development [98,99].

The increase in mucin protein levels may serve as potential biomarkers for tumorigenesis, although further research is needed to establish a direct link.

Another critical concern is the long-term effects of SARS-CoV-2 infection, known as long COVID-19. Prolonged infections could potentially predispose recovered patients to cancer development and accelerate cancer progression. Long COVID-19 has been associated with chronic low-grade inflammation and tissue damage, both of which are implicated in oncogenic processes [101]. The long-term inhibition of p53 and pRB by SARS-CoV-2 may also play a role in promoting cancer development in affected individuals.

However, it is important to note that SARS-CoV-2 differs from classical oncoviruses, which typically establish long-lasting infections contributing directly to cancer development. Most SARS-CoV-2 infections are resolved within a limited timeframe. Therefore, the role of SARS-CoV-2 as an oncogenic virus remains a topic of debate, and its potential to maintain extremely long-lasting infections contrasts with its putative role in cancer onset [101].

The Oncolytic Potential of SARS-CoV-2

Oncolytic viruses have emerged as a promising approach in cancer immunotherapy, as they can selectively infect and destroy cancer cells. These viruses have shown great potential in killing cancer cells while sparing normal healthy cells, making them an attractive option for cancer treatment [102,103,104,105,106].

The mechanism of action of oncolytic viruses involves their ability to replicate and spread within tumor cells, eventually leading to cell lysis and death [107,108]. This lytic process not only directly kills cancer cells but also releases tumor antigens, triggering an anti-tumor immune response [107,109].

Combining oncolytic viruses with immune checkpoint inhibitors, such as PD-1/PD-L1 antibodies, has been found to be particularly effective in enhancing the anti-tumor immune response, especially in cases where the cancer is resistant to PD-1/PD-L1 blockade therapy [109,110]. Interestingly, the antiviral response elicited by oncolytic viruses can also induce the synthesis of PD-L1 in the tumor environment, potentially contributing to immune evasion [27,110].

The oncolytic potential of SARS-CoV-2 has been a topic of interest, especially in relation to certain types of lymphomas. Patients with NK/T-cell lymphoma, a type of non-Hodgkin lymphoma, have been observed to have an increased expression of ACE2, the main receptor used by SARS-CoV-2 for cell entry [112]. This makes NK cells susceptible to SARS-CoV-2 infection, potentially leading to a decline in immune cell numbers and impairing immune surveillance [113].

Some interesting cases have been reported, showing transient remission of refractory NK/T-cell lymphoma during SARS-CoV-2 infection, with relapse occurring after COVID-19 resolution [111]. During acute SARS-CoV-2 infection, the viral load of EBV-DNA, used as a biomarker for NK/T-cell lymphoma, was found to decrease, only to recover after COVID-19 resolution. This suggests that the inflammatory response triggered by COVID-19 may have contributed to lymph node clearance, leading to the observed anti-tumor outcome in these lymphoma patients [27,111].

SARS-CoV-2 infection has also been associated with a potentially protective effect against Hodgkin lymphoma. A case study of a 61-year-old man diagnosed with EBV-positive classical Hodgkin lymphoma concurrently positive for SARS-CoV-2 infection showed reduced lymphadenopathy and decreased levels of tumor-related biomarkers after COVID-19 recovery, despite receiving no corticosteroid or immunochemotherapy treatments [114].

The hypothesis is that SARS-CoV-2 infection may have triggered an anti-tumor immune response due to the cross-reactivity of pathogen-specific T cells with tumor antigens and the activation of NK cells driven by the proinflammatory cytokine storm induced by COVID-19 [114].

The lessons learned from studying the oncolytic potential of SARS-CoV-2 and its interaction with the immune system could have implications for the development of novel therapeutic strategies based on oncolytic viruses. Combining the oncolytic characteristics of SARS-CoV-2 with genetic modifications to enhance T cell memory could potentially improve the immune response against known antigens to coronaviruses [27]. However, it is essential to note that the oncolytic effects of SARS-CoV-2 appear to be transient and non-specific, and further research is needed to understand the full extent of its oncolytic potential and how it can be harnessed for effective cancer treatment.

In conclusion, oncolytic viruses have shown promise as a potential cancer treatment strategy, and SARS-CoV-2 has demonstrated some oncolytic potential, particularly in certain lymphoma cases. The combination of oncolytic viruses with immune checkpoint inhibitors has the potential to enhance the anti-tumor immune response. However, much remains to be elucidated regarding the specific mechanisms of SARS-CoV-2’s oncolytic effects and its potential applications in cancer therapy. Further research and clinical trials are necessary to fully understand and harness the oncolytic potential of SARS-CoV-2 and other viruses for effective and targeted cancer treatments.


reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178366/

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