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Rapti, V.;  Tsaganos, T.;  Vathiotis, I.A.;  Syrigos, N.K.;  Li, P.;  Poulakou, G. SARS-CoV-2 and Cancer Cross-Talk. Encyclopedia. Available online: https://encyclopedia.pub/entry/32425 (accessed on 23 June 2024).
Rapti V,  Tsaganos T,  Vathiotis IA,  Syrigos NK,  Li P,  Poulakou G. SARS-CoV-2 and Cancer Cross-Talk. Encyclopedia. Available at: https://encyclopedia.pub/entry/32425. Accessed June 23, 2024.
Rapti, Vasiliki, Thomas Tsaganos, Ioannis A. Vathiotis, Nikolaos K. Syrigos, Peifeng Li, Garyfallia Poulakou. "SARS-CoV-2 and Cancer Cross-Talk" Encyclopedia, https://encyclopedia.pub/entry/32425 (accessed June 23, 2024).
Rapti, V.,  Tsaganos, T.,  Vathiotis, I.A.,  Syrigos, N.K.,  Li, P., & Poulakou, G. (2022, November 02). SARS-CoV-2 and Cancer Cross-Talk. In Encyclopedia. https://encyclopedia.pub/entry/32425
Rapti, Vasiliki, et al. "SARS-CoV-2 and Cancer Cross-Talk." Encyclopedia. Web. 02 November, 2022.
SARS-CoV-2 and Cancer Cross-Talk
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Since the pandemic’s onset, a growing population of individuals has recovered from SARS-CoV-2 infection and its long-term effects in some of the convalescents are gradually being reported. Although the precise etiopathogenesis of post-acute COVID-19 sequelae (PACS) remains elusive, the mainly accepted rationale is that SARS-CoV-2 exerts long-lasting immunomodulatory effects, promotes chronic low-grade inflammation, and causes irreversible tissue damage. Several viruses have been causally linked to human oncogenesis, whereas chronic inflammation and immune escape are thought to be the leading oncogenic mechanisms. Excessive cytokine release, impaired T-cell responses, aberrant activation of regulatory signaling pathways (e.g., JAK-STAT, MAPK, NF-kB), and tissue damage, hallmarks of COVID-19 disease course, are also present in the tumor microenvironment. Therefore, the intersection of COVID-19 and cancer is partially recognized and the long-term effects of the virus on oncogenesis and cancer progression have not been explored yet.

SARS-CoV-2 long-COVID post-acute COVID-19 sequelae post-acute sequelae of SARS-CoV-2 oncogenic pathways

1. Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that emerged in the city of Wuhan, China, at the end of 2019. Unlike SARS and Middle East respiratory syndrome (MERS) outbreaks that temporarily caused considerable global health consternation, SARS-CoV-2 continues to pose unprecedented challenges for healthcare systems and socioeconomic structures worldwide, since its precise pathophysiology is still poorly understood [1][2]. Lately, research has been focusing on the identification of the long-term consequences of COVID-19 on human health and the quality of life and its impact on pre-existing or emerging diseases, including cancer [3][4][5].
As expected, the systemic immunosuppressive status of cancer patients, whether caused by the disease itself or the anticancer treatment, confers an increased risk of COVID-19 compared to the general population [6][7][8]. Several studies point out that cancer patients experience a longer and severer COVID-19 disease course and higher mortality rates are also observed [6][9][10][11]. Notably, cancer type, staging, and therapeutics are determinants of SARS-CoV-2-associated morbidity and mortality [9][12][13][14].

2. Cytokine Release and Long-COVID

Cytokines play a crucial role in the evolution of infections, both microbial and viral, and determine the duration and severity of infections. Particularly for COVID-19, the course and outcome of the disease are determined by viral (mutational) and host (e.g., age, sex, comorbidities, and immunological) factors [15][16]. In SARS-CoV-2 infection, the innate and adaptive immune systems are activated following binding of the virus to the angiotensin-converting enzyme 2 (ACE2) protein of alveolar epithelial cells and subsequent production and interaction of chemokines, colony-stimulating factors, interferons, interleukins, and TNF-a. As vascular permeability increases, COVID-19 is developed [17][18]. When the immune response is dysregulated, it contributes to disease pathogenesis, as in the case of a “cytokine storm” [19][20], or hypercytokinemia, which is characterized by (a) perpetuated activation of lymphocytes and macrophages causing immune dysregulation, (b) large secretions of cytokines caused by such perpetuated activation, and (c) overwhelming systemic inflammation and multi-organ failure with high mortality [21][22]. The most important inflammatory mediators released by immune cells during the “cytokine storm” are IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-a, and TGF-β and they are associated with different clinical features of COVID-19 [15][23]. Indeed, cytokine storms correlate with the severity and progression of COVID-19 and can result in serious complications such as acute respiratory distress syndrome (ARDS) and multiple organ failure, which are the leading causes of death from the disease [24][25].
Shortly after the beginning of the COVID-19 pandemic, a phenomenon known as “long-COVID,” or post-acute sequelae of SARS-CoV-2 (PASC), appeared to medical professionals [26][27][28][29][30][31][32]. While COVID-19 symptoms are resolved in 1–4 weeks in the majority of patients, some patients complain of symptoms lasting longer than 28 days. These symptoms include fatigue, shortness of breath, headache (or “brain fog”), loss of smell (anosmia), sleep disturbances, fevers, gastrointestinal symptoms, anxiety, and depression and can persist for months and range from mild to disabling [33]. Even though a study on patients with pneumonia secondary to COVID-19 infection suggests that persistent symptoms may be attributable to “biopsychosocial” effects of COVID-19 (mainly due to the absence of residual radiographic abnormalities) [34], a number of studies have disclosed abnormal cardiopulmonary exercise testing [35], and most studies attribute the range of PASC symptoms to a number of differing pathological traits of the virus [36].
In the study by Queiroz et al., among patients in the post-COVID-19 group, subjects with PASC had higher levels of IL-17 and IL-2 and lower levels of IL-10, IL-6, and IL-4 than subjects without sequelae (i.e., without PASC symptoms/signs) [37]. The fact that pro-inflammatory cytokines were increased in the PASC group underlines the association of PASC with residual inflammation and inflammatory organ damage [38][39]. The higher levels of IL-10 and IL-4 in patients not suffering from PASC suggest better control of the inflammatory process due to increased levels of anti-inflammatory cytokines in these individuals. Furthermore, the significantly higher levels of IL-17 and IL-2 and lower levels of IL-4 and IL-10 in individuals with PASC suggest a possible “molecular signature” for PASC characterized by a Th17 inflammatory profile with a reduced anti-inflammatory response mediated by IL-4 and IL-10. In addition, since cytokines are prevalent in circulation, they are present in many different organ systems, and this explains the variety of symptoms associated with PASC. Nonetheless, since SARS-CoV-2 shows tropism for the nervous system and neurological manifestations (e.g., anosmia, ageusia, headache, stroke, Guillain–Barré syndrome, seizure, and encephalopathy) are observed in the majority of patients with acute COVID-19, microvascular inflammation in cells of the nervous system during acute infection may trigger mild symptoms of the disease [40], which may persist even after the infection has resolved.
In the study by Schultheiss et al., PASC appeared in up to 60% of the patients up to 24 months post-infection; elevated levels of IL-1β, IL-6, and TNF-a were detected in those patients with their most probable source of secretion being the monocytes and macrophages of the lung [41]. Similar results were observed in the study by Peluso et al.: higher levels of IL-6 and IFN-γ-induced protein 10 (IP-10) during early recovery from COVID-19 were associated with subsequent development of PASC; in addition, among patients with PASC, IL-6 showed a trend towards from early to late recovery [42]. Similar findings were noted in the study by Acosta-Ampudia et al., where a pro-inflammatory state was observed in patients with PASC characterized by up-regulated IFN-α, TNF-a, granulocyte colony-stimulating factor (G-CSF), IL-17A, IL-6, IL-1β, and IL-13, whereas IP-10 was decreased [43]. In yet another study, several cytokines from interferon I and III classes were highly elevated and stayed up for over 8 months [44].
The differences in the results among the previous studies could be attributed to methodological differences, e.g., different time-points of cytokine determination, population size, and characteristics (e.g., country, severity of acute COVID-19). Nonetheless, the paramount finding is a persistent and diffuse proinflammatory state and a dysregulated cellular immune response, which is compatible with two of the currently most discussed hypotheses on the immune pathogenesis of PASC: (a) ongoing immune responses against persisting virus or viral antigens and/or (b) chronic reprogramming of immune cells [37][41][42][43][44].

3. T-Cell Response and Long-COVID

The immune system is broadly divided into the innate immune system and the adaptive immune system. The adaptive immune system is important for the control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells (they possess a range of helper and effector functionalities), and CD8+ T cells (they kill infected cells). Adaptive immune responses are slow due to the intrinsic requirement of selecting and expanding virus-specific cells from the large pools of naive B cells and T cells: they take 6–10 days after priming to generate sufficient cells to control a viral infection, due to the inherent time demands for extensive proliferation and differentiation of naive cells into effector cells. Once sufficient populations of effector T cells (Th cells and CTLs) and effector B cells (antibody-secreting cells, known as plasmablasts and plasma cells) have proliferated and differentiated, they often work together to rapidly and specifically clear infected cells and circulating virions [45]. In a SARS-CoV-2 infection, the virus is particularly effective at avoiding or delaying triggering intracellular innate immune responses associated with type I and type III IFNs [46][47][48][49]. Without those responses, the virus initially replicates unabated and the adaptive immune responses are delayed, so that an asymptomatic infection or clinically mild disease follows; this is because the T cell and antibody responses occur relatively quickly and control the infection. Whenever impaired and delayed type I and type III IFN responses occur, the virus replicates heavily in the upper respiratory tract and lungs (due to failure of adaptive immune response priming) and a very high risk of severe or fatal COVID-19 ensues [50][51][52][53][54].
In PASC patients, the following findings have been observed: increases in antigen-specific CD4+ T cell responses to the SARS-CoV-2 S protein, antigen-specific activation in the circulating T follicular helper cells, and populations of CD8+ T cells (mainly attributed to their effector subpopulation). All these data show a prolonged T cell response magnitude [55], which eventually leads to exhaustion of T cells, as indicated by the increased expression of exhaustion markers, namely PD-1-expressing T lymphocytes [56][57][58]. Interestingly, T cell exhaustion can be reversed and T cell function can be restored by PD-1 blockade, which in turn ex vivo increases the CD4+ T cell-mediated response to SARS-CoV-2 spike and nucleocapsid peptides [56]. Another feature of PASC is the lower and more rapidly waning N-specific CD8+ T cell responses (IFNγ-/CD107a+ and IFNγ+); this lower frequency of degranulating virus-specific CD8+ T cells in individuals with PASC could be attributed either to the decreased functional capacity of these cells or dysfunction of the immune response [59]. Another feature of PASC is the significantly increased level of Tregs (CD4+ CD25+ CD127 low): this can be explained in the light of the increase in the PD-1-expressing T lymphocytes, indicating failing attempts of the immune system to control the persistent immune response [58]. Towards a better understanding of the pathophysiology of PASC, it has been suggested that T-cell subsets exhibit different dynamics, depending on the severity of the initial infection and the time since then; in severe convalescents, there is a tendency towards an exhausted/senescent state of CD4+ and CD8+ T cells and perturbances in CD4+ Tregs 3 months post-infection, a remodeling that is clearly visible at 6 months post-infection. In addition, CD8+ T cells exhibit a high proportion of CD57+ terminal effector cells, together with a significant decrease in the naive cell population, augmented granzyme B and IFN-γ production, and unresolved inflammation 6 months post-infection. On the contrary, mild convalescents showed increased naive Tregs, and decreased central memory and effector memory CD4+ Treg subsets [60].
Apart from circulating T and B cells, there are tissue-resident memory cells that reside in the peripheral non-lymphoid tissue [61][62]; those cells provide immediate and superior immunity against viral reinfections [63]. However, dysregulated lung-resident T cell responses may cause chronic lung inflammation and fibrosis after respiratory viral infection [64][65]. In line with those findings, Cheon et al. have found that exuberant CD8+ T cell responses may be connected to the development of chronic lung sequelae after the resolution of acute COVID-19 infection in aged individuals [66].

4. Tissue Damage and Long-COVID

The recent coronavirus outbreaks (SARS epidemic of 2003 and MERS outbreak of 2012) have demonstrated that persistent respiratory symptoms and radiographic abnormalities continue beyond the period of acute illness. In a considerable number of these patients post viral sequelae in the form of lung fibrosis have been reported. Given the genetic homology between SARS-CoV-2 with both SARS and MERS and the increased infected population worldwide during the current pandemic, it can be assumed that an increased likelihood of post-COVID-19 long-term pulmonary complications, and particular lung fibrosis, is expected [67]. In COVID-19 survivors, more than one-third describe respiratory symptoms in the context of PASC; of those greater at risk are females, who had severe acute COVID-19 disease and/or required invasive or noninvasive ventilation.
Pulmonary fibrosis can occur in the setting of maladaptive resolution of lung injury or exaggeration of the reparative process [68]. Fibroblasts respond to alveolar injury and secrete the extracellular matrix; during acute infection and the post-COVID period they are overreactive due to the upregulation of inflammatory cytokines and this results in distortion and remodeling of the pulmonary architecture. Monocyte-derived alveolar macrophages (MoAMs) are profibrotic and stimulate and form reciprocal circuits with fibroblasts [69]; the maladaptive repair of the alveolar injury results in a positive feedback loop that results in filling the alveolar interstitium and alveoli with matrix proteins and fibroblasts. In this setting, PASC-pulmonary fibrosis may develop following a prolonged phenotype of a slowly unfolding, spatially limited inflammatory alveolitis [70]. The prolonged exposure of profibrotic monocytes to elevated levels of cytokines results in intense interaction with fibroblasts to promote fibrotic repair processes. Altogether there is concern that the protracted nature of acute COVID-19, persistence of high levels of cytokines, monocyte/macrophage and T-cell circuits stimulating potential circuits between monocytes and fibroblasts, coupled with the extended duration of mechanical ventilation, could combine to promote a milieu in the alveoli with an increased likelihood of PASC-pulmonary fibrosis [43]. SARS-CoV-2 can also impose lung tissue damage by impairing microcirculation with a number of mechanisms [71]: capillary pericytes are damaged in COVID-19, thus hindering lung repair and neo-angiogenesis; endothelial cells (EC) become apoptotic and protrude in the lumen; capillary endothelium glycocalyces’ are shed; capillaries are obstructed by circulating neutrophils, by microthrombi formation or by fibrin-rich amyloids formation which are resistant to fibrinolysis [72][73].
Blood microcirculation disturbances during COVID-19 and subsequent tissue damage that may contribute to PASC can also affect other organs [71]. In the heart, endothelial infection results in EC swelling in small vessels and scattered necrosis of individual myocytes. In the brain, infection of subcortical white matter microvessel endothelium is associated with hyper-acute, microscopic ischemic lesions, and older ischemic and hemorrhagic microscopic lesions. In the skin, EC infection is associated with endothelial swelling and in some patients with thrombosis and fibrinoid necrosis in surrounding tissue. Keeping in mind that erythrocyte diameters are bigger than the capillary lumen, endothelial damage is likely to disturb capillary flow patterns in all affected organs, resulting in extreme shunting of oxygenated blood through the shortest capillary pathways. Thus, it has been proposed that COVID-19 is an endothelial disease and PASC may have its origins in subsequent tissue hypoxia [71][74].
Tissue damage has been disclosed in many organs of convalescent people, even in young ones, mostly free of risk factors for severe COVID-19: more than half of them had at least one radiographic abnormality of the lungs, heart, liver, pancreas, kidneys, or spleen and these abnormalities could persist for at least 2–3 month after hospital discharge [75]. Although not a pure tissue damage, gut microbiome disruption (i.e., gut dysbiosis) has been observed among patients with COVID-19 and persists even after disease resolution. Gut dysbiosis is also correlated with increased COVID-19 severity and inflammatory biomarkers and prolonged SARS-CoV-2 [76]. It has also been postulated that the gut microbiome modulates the neurotransmitter circuitries in the gut and brain via the microbiota gut–brain axis.

5. Oncogenic Pathways and SARS-CoV-2

As discussed above, viruses interfere with the DDR network by recruiting DNA damage proteins to viral replication centers and regulating apoptosis via repair pathways suppression. As such, SARS-CoV-2 non-structural protein 1 (NSP1) has been shown to interact with all four members of DNA polymerase alpha (Pol a), an essential complex that is involved in the initiation of DNA replication and couples cycle cell progression to DRR [80]. Like other RNA viruses, in order to be replicated and escape immune surveillance, SARS-CoV-2 manipulates directly or indirectly mitochondrial metabolism, a key component of cellular homeostasis maintenance and cancer pathophysiology, by interfering with mitochondrial proteins [81]. Gordon et al. reported the interaction of SARS-CoV-2 ORF9c, a membrane-associated protein enabling immune evasion, with electron transport chain (ETC) components, suggesting a possible role as an oxidative phosphorylation regulator [80]. It is worth mentioning that ETC induces oxidative stress, as well. SARS-CoV-2 NSP8 and NSP5 have been proposed by Tutuncuoglou et al. to interact with histone methyltransferase NSD2 and HDAC2, respectively, and the latter have been linked to several oncogenic pathways [77][82]. For example, both of them are involved in NF-kB activation by proinflammatory cytokines, whereas NSD2 overexpression results in oncogenic RAS-driven transcription in lung cancer cells, and HDAC2 is a coactivator of the tumor suppressor p53 [83][84]. Lastly, the SARS-CoV NSP3 and NSP15 have been implicated in the degradation of p53 and pRb, respectively, and the SARS-CoV-2 S2 subunit has been demonstrated in silico to interact with p53 and BRCA 1/2, granting genomic instability [85][86][87]
Immune dysregulation, a hallmark of COVID-19 course and severity, is mainly orchestrated by cytokines and chemokines (e.g., IL-6, IL-1β, IL-8, IL-18, TNF-a) that are identified as tumorigenesis drivers [88]. Additionally, multiple signaling pathways (e.g., IL-6/JAK/STAT, NF-kΒ, IFN-Ι), which are prominent in oncogenesis, have been proved to contribute to COVID-19 etiopathogenesis, as well [78]. For instance, aberrant IL-6/JAK/STAT-3 signaling potentiates inflammatory responses in COVID-19, therefore aggravating disease severity; in the context of cancer, it attenuates anti-tumor T-cell mediated responses and favors tumor growth, survival, invasiveness, and or/metastasis [89]. Furthermore, the NF-kB pathway has been documented to be hyper-activated in moderately or critically ill COVID-19 patients and it is characterized as a crosstalk mediator between inflammation and cancer [90]. The NF-kB pathway is capable of remodeling the immune landscape to benefit tumor proliferation, inhibiting apoptosis and attracting angiogenesis [90]. Impaired IFN signaling, which underlies severe COVID-19, employs pro-tumoral properties and it is assumed as a key mechanism in tumor proliferation [91]. IFNs have been reported to trigger the NF-kB pathway, protect cells against apoptotic stimuli and foment angiogenesis [91][92][93]. Interestingly, IFNs harbor immunoevasion by decreasing sensitivity to NK cells and downregulating tumor-associated antigen presentation and contribute to drug resistance via IFN-related DNA damage-resistant signature (IRDS) induction [91][94].
It is no surprise that SARS-CoV-2 and tumor cells interfere with similar signaling pathways to their advantage. mTOR pathway displays fundamental functions (e.g., proliferation, metabolism, protein synthesis, autophagy, and apoptosis) and it is perturbated in cancer [95]. SARS-CoV-2 is also known to exploit mTOR signaling and at least seven targets have been identified so far [96][97]. The Notch pathway, a highly conserved signaling pathway that controls multiple cell differentiation processes, is an attractive target in COVID-19 and its overexpression enhances viral entry and the manifestation of inflammatory, coagulopathic and hypoxic events [98]. In addition, it is one of the most commonly activated signaling pathways in different cancer types and emerging data highlight its contribution to invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues [99][100]. The p38 MAPK pathway allows cells to interpret and respond to various signals and stimuli, such as DNA damaging genotoxic agents, inflammatory cytokines, oxidative stress, and heat shock [101]. In COVID-19, it has been stated as disproportionately upregulated as a result of ACE2 activity loss upon viral entry or/and direct viral activation of p38 MAPK; the activated p38 MAPK pathway facilitates viral entry via ACE2 endocytosis and predisposes for pathological processes, such as inflammation and thrombosis [102]. Dysregulated p38 MAPK signaling is implicated in a wide range of cancers and it oversees the expression and the deposition of pro-angiogenic and pro-tumorigenic factors aiding in carcinoma growth, metastasis, and treatment resistance [101][103].
Persistent tissue hypoxia, derived by hyperinflammation or SARS-CoV-2-induced ACE2 depletion, promotes oxidative stress and genomic instability. Within predisposed cells, the proteomic and genomic changes may initiate cell cycle arrest and apoptosis evasion, while they facilitate tumor overgrowth, invasion, and metastasis [104][105]. In the case of SARS-CoV-2-mediated oxidative stress, NO overproduction alongside bradykinin degradation stimulates EGFR signaling, which is commonly upregulated in diverse carcinoma types [96].

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