Epstein–Barr Virus-Associated Nasopharyngeal Carcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/medicina59010002

Nasopharyngeal carcinoma (NPC) is an uncommon type of malignancy/cancer worldwide. However, NPC is an endemic disease in southeast Asia and southern China and the reasons behind the underlying for such changes are unclear. Even though the Epstein–Barr infection (EBV) has been suggested as an important reason for undistinguishable NPC, the EBV itself is not adequate to source this type of cancer. The risk factors, for example, genetic susceptibility, and environmental factors might be associated with EBV to undertake a part in the NPC carcinogenesis. Normal healthy people have a memory B cell pool where the EBV persists, and any disturbance of this connection leads to virus-associated B cell malignancies. Less is known about the relationship between EBV and epithelial cell tumors, especially the EBV-associated nasopharyngeal carcinoma (EBVaNPC) and EBV-associated gastric carcinoma (EBVaGC). It is believed that premalignant genetic changes in epithelial cells contribute to the aberrant establishment of viral latency in these tumors. The early and late phases of NPC patients’ survival rates vary significantly. 

Epstein–Barr virus virus carcinoma nasopharyngeal carcinoma oncogenic viruses

1. Introduction

The Epstein–Barr virus (EBV), which is sometimes also referred to as human herpesvirus 4, is a member of the herpes virus family [1]. It is one of the most prevalent viruses in humans and may found worldwide. The majority of individuals become infected with EBV at some point in their life [2]. The EBV infection is frequently transmitted by bodily fluids, particularly saliva. EBV might be responsible for diseases such as infectious mononucleosis, and some other diseases [3][4].
Children are most often infected with EBV [5]. Most of the time, pediatric EBV infections do not cause symptoms, or if they do, those symptoms resemble those of other mild, temporary childhood disorders [2][6]. Usually in adults or teenage patients, those with EBV infection symptoms heal in two to four weeks. However, for some people, fatigue may last for many weeks or even months. After contracting EBV, the virus goes into a latent (inactive) state. The virus may sometimes reactivate. Although symptoms are not always present, those with compromised immune systems are more prone to have them if EBV reactivates [7]. Saliva in particular is a frequent bodily fluid through which EBV might be transmitted, but EBV may also be transmitted by organ transplants, blood transfusions, and through blood or semen during sexual intercourse. EBV can also be transmitted through items that an infected person recently used, such a toothbrush or drinking glass. The virus most likely persists on an item for at least as long as it is moist. The host might spread the virus for weeks or even before symptoms appear after contracting EBV for the first time (primary EBV infection) [8][9].
Both the eradication of viral infections and the inhibition of tumor development depend critically on the activation of inflammasomes and the subsequent inflammatory response [10]. Chronic inflammation, which promotes the growth of tumors and virus replication, is caused by abnormal production of proinflammatory cytokines as a result of dysregulated inflammasome signaling. Due to its inhibitory activity against ongoing inflammation, which may make diseases worse, and by giving a chance to increase the effectiveness of immune checkpoint blockade in cancer immunotherapy, targeted inhibition of inflammasome activity may have potential applications in cancer prevention and therapy [11][12]. Inflammasome-mediated antitumor immune responses are evaded by viruses using a variety of tactics, according to research published recently. The evasion mechanisms in EBV-associated malignancies, however, still need much more research [13]. Furthermore, nothing is known about the clinical function of NLR inflammasomes in response to EBV infection. Prior to this, the divergent impacts of inflammasomes in cancer further imply that there is more to learn about the functional roles and processes involved [14][15].
The genome of EBV is 172 kb long which encodes almost 100 open reading frames (ORFs) [16]. These ORFs are divided into lytic and latent genes. The latent proteins consist of three latent membrane proteins (LMP1, LMP2A, and LMP2B) and six nuclear antigens [17].

2. Definition of Nasopharyngeal Carcinoma

A very rare type of carcinoma, which belongs to head and neck cancers, is nasopharyngeal carcinoma (NPC) [18]. It was also known as lymphoepithelioma previously. NPC originates in the nasopharynx which is an upper respiratory tract organ located behind the nose, above the back of throat and near to the Eustachian tubes [19]. Due to this complicated anatomic location and great radiosensitivity, for the treatment of non-metastatic or stage I NPC, radiation therapy (RT) is strongly advised [20]. However, the majority of patients only receive a diagnosis after the disease has progressed, since early-stage NPC symptoms such as headache, nosebleed, nasal blockage, and nasal discharge are benign. Southeast Asia has a higher prevalence of NPC cases, which are commonly but not always associated with EBV [21][22].
Based on how the tumor cells look under a light microscope, the World Health Organization (WHO) has classified NPC into two basic histological types. One is keratinizing squamous cell carcinoma (type I) and the other is non-keratinizing squamous cell carcinoma (type II and type III). Differentiated non-keratinizing carcinoma (type II) and undifferentiated carcinoma (type III), which are mostly EBV-positive tumors, are additional subtypes of the non-keratinizing type [23]. Less than 20% of NPC cases globally are well-differentiated keratinizing NPCs (type I), and this tumor type is rather uncommon or not present in the southern part of China. However, it has been shown that EBV is notably associated with the WHO type I, more differentiated form of NPC in the areas with a high frequency of undifferentiated NPC [24]. In NPC, the virus only lives in the tumor cells in a latent condition; it is not present in the lymphoid infiltrate around the tumor [25]. However, the interaction between the nearby carcinoma cells and the protruding lymphoid stroma seen in undifferentiated NPC seems to be essential for the continuing proliferation of malignant cells of NPC [26][27].

2.1. Staging of NPC

The American Joint Committee on Cancer (AJCC) re-evaluated the staging procedure in 2018 due to the variations in imaging technology and better results linked to optimal medication [22]. Recent recommendations have established the definitions for the tumor node metastasis (TNM) classification of malignant tumor staging as primary tumors (T), nodal metastasis (N), and distant metastasis (M) [21]. The staging of EBV has been elaborated in Figure 1.
Figure 1. The tumor node metastasis (TNM) staging for nasopharyngeal carcinoma (NPC).

2.2. Diagnostic Features of NPC

The early detection of NPC is challenging, possibly because it is difficult to inspect the nasopharynx and because the symptoms of NPCs might be mistaken for those of other, more prevalent illnesses [28][29]. A more precise immunofluorescence method was developed to recognize antigens against replicative antigens encoded by EBV, and this test confirmed the correlation between higher antibody titers against the membrane antigen (MA) and EBV-encoded viral capsid antigen (VCA) with NPC [30][31]. Later, using the DNA hybridization technique EBV DNA was identified in the samples from NPC tumors. The serological analysis revealed a correlation between the EBV antibodies titers and the NPC tumor stage, as well as the particular IgA levels of VCA as a potential visualization pointer. The in situ hybridizations identified EBV DNA in the NPC growth cells but not in cells such as lymphoid penetrating cells [32][33].
In view of the obvious explicitness of the connection between the degrees of IgA of VCA and NPC, a mass serological location program in the city of Wuzhou, China was conducted in 1980, where it was shown that EBV-explicit antibodies are valuable for NPC’s initial distinguishing proof [34]. The exploration showed the presence of IgA viral capsid antigen as early as 3 years and 5 months before the clinical conclusion of NPC. Southern exchange hybridization of terminal repeats (TRs) in the EBV genome in NPC showed that occupant viral genomes were monoclonal, proposing that EBV disease happens before the clonal development of the inhabitants in malignant growth cells [35][36].
Using electronic microscopy, the particles of herpes virus in a subset of tumor cells derived from Burkitt lymphoma (BL) were detected [6][37]. After a few years, the antibodies were found in the blood of African patients with BL who showed antigens delivered by BL cells. The serum of patients with post-nasal space carcinoma displayed comparable BL antigen antibodies [38]. These antibodies were distinguished in an enormous number of African and American patients. The significant prevalence of positive sera among patients with post-nasal area carcinoma highlights the necessity to differentiate comparable particles in cancer-prevalent areas [22][38].

2.3. Morphological Similarity of Undifferentiated Carcinomas of Nasopharyngeal Type (UCNT)

The discovery of EBV in UCNT has motivated many organizations to investigate undifferentiated NPCs [39]. Stomach UCNTs are consistently positive for EBV, but the other UCNTs have a lower association with EBV [40]. Previously, EBV has been identified in Chinese patients with thymic epithelial tumors but not in Western patients. Additionally, whereas Caucasian patients do not have an association between UCNTs of the salivary glands and EBV, Greenlanders and Chinese patients do. UCNTs from the uterus and breast are free from EBV in a few cases [41][42].
EBV is a two-fold strand DNA infection with a genome from 170 to 180 kB which contains almost 100 qualities for a dormant or lytic disease of host cells [18]. The viral genome remains episomal during the latest stage of the disease. It activates a number of latent genes (>10) that are used to control different cellular processes and make use of the host’s DNA polymerase enzymes for the process of DNA replication [43]. Meanwhile, during necessary cell death, lytic infection causes the production of >80 lytic proteins and the release of virus particles into the extracellular space [44]. Despite the fact that EBV is now categorized as a category I carcinogen, more than 90% of healthy persons are lifetime carriers of the illness. Only a few memory B cells in healthy people retain EBV latency after initial infection, which is regulated by the host’s immune system [45]. To start tumors and promote clonal growth of infected lymphoid and epithelial cells, the virus, however, causes specific epigenetic/genetic modifications or impairs the host immune system [46].
EBV is the main human oncogenic infection to be recognized. It is connected to classic Hodgkin’s lymphoma (HL), Burkitt lymphoma (BL), B cell lymphoma (BcL), NK/T cell nasal lymphoma, two sorts of epithelial carcinoma, gastric disease (e.g., GC), and cellular breakdown in the lung’s cells (e.g., NPC) [47]. For GC and NPC, 84,000 and 78,000 cases of the 200,000 newly reported cases of lethal cancers related to EBV are diagnosed every year, respectively [48]. Stomach malignant growths brought about by EBV are under 10% of all stomach diseases and are not endemic. In endemic locales such as Hong Kong and southern China, practically all non-keratinizing NPCs are consistently connected with EBV disease [49]. Studies in the last thirty years have laid out that EBV contamination and different hereditary irregularities are the motors of the threatening growth of NPC. It is accepted that NPC is a clonal dangerous cancer from a solitary inert contaminated progenitor cell caused by EBV [50]. Every EBV study supports this idea. Similar numbers of TRs are present in the episomal genomes of NPC cells, which rules out the possibility of progenitor cell inactive replication due to EBV. The unstoppable virions’ linearized genomes are circularized by irregular and discontinuous episome formation throughout the EBV lytic cycle and this results in contamination of epithelial cells, resulting in a varied number of TRs in each EBV episome within the infected cell [51][52].

3. Symptoms and Transmission

NPC may not cause any symptoms in its early stages [53]. Possible noticeable symptoms of NPCs include:
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Neck lymph node enlargement.
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Bleeding from the mouth or nose.
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Ear-related issues and hearing loss caused by the tumor’s closeness to the Eustachian tube, which causes obstruction and fluid collection in the middle ear.
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Sore throat.
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Difficulty breathing through the nose.
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Headache.
Oncogenic viral infections are thought to play a key role in the development of 20% of all types of human cancers, or about 2 million cases every year [54]. Infection’s function in cancer research reveals the fundamental apparatuses which can initiate neoplastic progression and points to healing and preventative options. The first human tumor virus to be discovered was Epstein–Barr virus (EBV), and it has revealed a lot about cancer etiology and it also has the usual antiquity of chronic herpes virus septicity [55]. EBVaNPC, in many cases, is the cause of illness and mortality in China. Despite NPC’s high public health impact in regions where NPC is identified and prevented, the NPC risk factors include eating highly salt-preserved seafood and tobacco use [56]. In China, EBV accumulates in undifferentiated NPC (most NPCs). Individuals develop EBV cancer even though it affects the majority of humanity, suggesting that EBV alone is not enough to cause cancer [57][58].
An IgA antibody against Epstein-1 (EBNA1/IgA) and VCA/IgA assessed by enzyme-linked immunosorbent assay (ELISA) has higher specificity, sensitivity, and positive predictive value than other techniques, according to a recent study [22]. According to EBV serological markers, individuals diagnosed as having a high risk of NPC can be offered fiberoptic endoscopy/biopsy to lower mortality [59]. New biomarkers, both cost-effective and labor-effective, are needed to identify high-risk groups to serve the NPC community better [60].
Regarding transmission:
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The most common method of EBV transmission is via bodily fluids, notably saliva. EBV may, however, be spread by blood and sperm during sexual activity, blood transfusions, and organ transplants.
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EBV may be transmitted by touching an infected individual’s recently used drinking glass or toothbrush. The virus is likely to live on a surface for as long as it stays moist.
When infected with EBV for the first time (primary EBV infection), the virus may spread for many weeks prior to the onset of symptoms [61]. The virus stays latent inside the body (inactive). One may possibly transmit EBV to others if the virus reactivates, regardless of how long it has been since the first infection [62]. NPC is an uncommon head and neck tumor that begins in the nasopharynx. The nasopharynx is positioned at the very back of the nose, near the Eustachian tubes. EBV is common but not always the cause of NPC in Southeast Asia [63].

4. Latent Gene Products of EBV

Both of the EBV latent gene products (the EBERs and LMP1) and homogeneous lengths of TRs were previously discovered in NPC and precancerous lesions [64]. It was suggested that the clonal latent EBV infection is a key contributor to the development of these virus-related cancers. Additionally, earlier genomic and functional studies demonstrated that a number of specific genetic alterations in the premalignant nasopharyngeal epithelium support a cellular switch to a state that maintains persistent latent EBV infection and predisposes people to NPC transformation (such as the inactivation of CDNK2A/p16 and tumor suppressors at chromosome 3p) [65][66]. In actuality, latent EBV infection persistence and latent viral gene production are required for NPC formation. Examples of type II latency programs discovered in NPC include LMP1, LMP2, EBNA1, EBER1/2, and BARF1, several splicing non-coding RNAs, and a variety of miRNAs expressed in BART regions. While latent genes such as LMP1 and LMP2 are expressed in various ways in the tumor or when the illness worsens, EBERs and EBNA1 are present in all cancer cells [67][68].
While the EBV genome is lost during the long-term passage of different NPC in vitro cell lines, the dormant EBV disease is ceaselessly distinguished in every growth cell in xenograft models from patients and the NPC clinical tissues in both the fundamental and principal repeating textures in essential and repeating cases [69][70][71]. The existence of an EBV episomal genome and the necessity for a very large number of viral characteristics for detrimental alteration are among the key characteristics of EBVaNPC. As indicated by overviews, numerous viral inert qualities have been found to contribute to the cancer genesis of NPC by providing an assortment of malignant growth attributes [72]. Throughout recent years, epithelial cell lines have been utilized to concentrate on the cancer-causing properties of these dormant quality items and their part in the carcinogenesis of NPC [73]. The replication and the mitotic isolation of EBV episomes, as well as the safeguarding of EBV genomes in inert contaminated cells, all rely upon EBNA1. Additionally, it is demonstrated that EBNA1 upholds cell endurance after DNA harm by instigating genomic insecurity and initiating a few cell qualities through transcriptional enactment [74][75].
EBNA1 is only one of the numerous non-polyadenylated RNAs found in certain EBV malignant growth cells, which incorporate EBER1 and EBER2. In latent infected epithelial cells, the EBERs self-replicate and bind to the ribosomal protein L22 to deliver ribonucleoprotein particles [76][77]. The complex then connects to the PKR, hindering apoptosis by FAS. Additionally, these non-coding RNAs have shown the ability to promote growth improvement by enhancing IGF-1 autocrine production and activating the NF-B pathway through RIG-1 and TLR3 flagging [78]. Numerous multi-locus, non-long coding records, and viral components from BAMH1 are produced by NPC cells, a member of the EBV family. EBV-encoded miRNAs, often referred to as miR-BARTs, target a variety of viral and cellular genes in order to promote cell proliferation, enhance invasiveness, inhibit apoptosis, create genomic instability, and disrupt the apoptotic host immune response [79].

5. Primary Gene Product (Genetic Variability)

EBV infects B lymphocytes at the start of primary infection, but it is not clear where these cells are infected or if the infection also affects the higher respiratory epithelial cells. EBV colonizes the pool of memory B cells to develop long-term persistence in vivo. A latent infection is created, which is identified by the expression of a small subset of viral genes known as latent genes [43]. Different types of EBV latency exist. The virus mimics latency models seen in certain malignant tumors linked to EBV and utilizes them for various viral life cycle stages [11]. EBV must also multiply periodically during its life cycle to generate infectious virus for transmission to a new sensitive host, with epithelial regions in the oropharynx and salivary glands showing the main viral replication sites [80]. Thus, the natural history of chronic EBV infection is comparable to that of another herpesviruses. To express the latent and replicative forms of the viral life cycle, many cell lines are required [81].
When looking at tumor types connected to the virus, the dual tropism of EBV infection is clear. The in vivo memory B cell pool may be infected by EBV. In vitro, inactive B cells can be quickly transformed into infected lymphoblastoid cell lines (LCLs), which resemble several malignant B cell tumors closely associated with EBV [82]. However, the undifferentiated type of nasopharyngeal cancer has a strong association with EBV (NPC). EBV is also present in a subset of gastric adenocarcinomas and other carcinomas of the salivary glands. As a result, EBV epithelial infection can cause malignant transformation, requiring specific preventive and therapeutic treatments [74][76].

6. Risk Factors

The etiology of NPCs has been a mystery for more than a century since it was initially reported in 1901. Studies of southern Chinese migrants demonstrate that the incidence of NPCs is 10 to 30 times higher than that of other races when they settle in other countries, an unusual trend among malignant tumors that suggests a heredity component of the risk of NPC [83]. Contrasted with local Israelis and local Swedes, North African outsiders in Israel and Sweden had a higher recurrence of NPC. Despite the fact that around half of individuals living in China or moving to Southeast Asia have NPCs, the recurrence is significantly higher among Chinese born in Western nations than Caucasians [77]. Likewise, contrasted with French men born in the south of France, French men born in North Africa had a higher risk of NPC [80].
A family history of NPCs and some natural variables appear to assume a vital role in NPCs, as shown by the most recent examinations. The risk factors include Cantonian ethnicity, male sex, EBV disease, routinely eating fish preserved in salt, low utilization of new vegetables and natural products, smoking, and certain antigen classes of human leukocytes (HLA) [83]. Other HLA genotypes, such as with a history of infectious mononucleosis (IM), can be related to a decrease in risk. History of chronic respiratory illnesses, high intake of other preserved foods, and genetic polymorphisms in cytochrome CYP2A6, P450 2E1 (CYP2E1), GSTT1, and glutathione S-transferase M1 (GSTM1) are additional possible risk factors. Herbal drug use, occupational exposure to dust and formaldehyde, and nickel exposure are less well-established risk factors [77].

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Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Naveed Ahmed
,
Mai Abdel Haleem A. Abusalah
,
Anam Farzand
,
Muhammad Absar
,
Nik Yusnoraini Yusof
,
Ali A. Rabaan
,
Hajir AlSaihati
,
Amer Alshengeti
,
Sara Alwarthan
,
Haifa S. Alsuwailem
,
Zainb A. Alrumaih
,
Ahmed Alsayyah
,
Chan Yean Yean
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Update Date: 29 Dec 2022
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