LMP-1 gene is an essential oncogene, which is expressed as a constitutively active receptor in a majority of EBV associated tumor cells [ 62 ].
LMP-1 is a amino acid protein with a short cytoplasmic N-terminal domain, six transmembrane spanning domains, and a amino acid long C-terminal cytoplasmic domain [ 63 ]. The N-terminal domain tethers the LMP-1 on the surface of the plasma membrane, and oligomerization as well as self-aggregation of the protein is mediated by the six trans-membrane spanning domain. Previous reports have shown that these two functional domains interact with intracellular signaling proteins such as tumor necrosis factor TNF receptor-associated factor TRAF -1, -2, -3, -4, -5, and -6 found in tumor necrosis factor receptor TNFR signaling pathway in B cells and epithelia cells [ 65 , 66 ].
The activation of these major signaling pathways results in the up-regulation of expression of antiapoptotic proteins such as A 20, Bcl-2, and down-regulation of tumor suppressor protein, p53, promoting cell growth and survival [ 70 , 71 ]. Biological activities of latent membrane protein-1 LMP-1 in tumorigenesis. EBV LMP-1 activates cellular pathways that lead to tumor invasiveness and metastasis, cell proliferation, and inhibition of apoptosis.
Structurally, both proteins have 12 trans-membrane domains and a 27 amino acid cytoplasmic C-terminal domain, however, LMP-2A has an additional amino acid cytoplasmic N-terminal domain, which is not found in LMP-2B [ 75 ]. The BCR-like signaling, mediated by LMP-2A, provides strong survival signal which rescues BCR-negative cells from apoptosis [ 78 , 79 ] and inhibit signaling that leads to lytic reactivation [ 80 ]. LMP-2A has been shown to be essential for activation, proliferation, and survival of EBV infected B cells at early times, after which it is required for long term growth of B cells [ 81 ].
The function of LMP-2B on the other hand, is not clearly known [ 81 ], but a previous report has shown that it interacts with LMP-2A to modulate the activities of the latter [ 75 ]. The virus has been found to express 44 miRNAs in all forms of latency and tumor tissues, regulating both cellular and viral genes [ 86 ]. EBV is implicated in several malignancies ranging from epithelial and lymphoid origins. Biochemical, serological, and molecular methods to detect EBV have increasingly become necessary in the diagnosis and monitoring of patients with EBV-associated diseases [ 98 ].
Serological assays, that are used to identify the virus in infected individuals, involve the detection of antibodies against EBV specific antigens such as viral coat antigen VCA , EBNA-1, early antigen EA and viral nucleic acids [ 99 - ].
Detection and quantification of EBV nucleic acids in body fluids and tissues using polymerase chain reaction PCR have also been exploited for diagnosing and monitoring of EBV-associated diseases [ ]. The different malignancies are shown in Figure 4. The virus in the various target cells expresses different patterns of latency genes and these determines the type of cancer that would be developed.
B cell derived lymphomas include Burkitt lymphoma, Hodgkin lymphoma, and posttransplant lymphoproliferative disorders which are caused by the expression of latency I, II, and III, respectively, gene products.
Infection of epithelia cells by EBV results in cancers such as nasopharyngeal, breast, and gastric cancers, caused by the expression of latency II, II, I, respectively, gene products. Full details of each tumor are further described below. Burkitt's lymphoma BL is a highly aggressive non-Hodgkin B cell neoplasm and is the world's commonest pediatric cancer; endemic in Sub-Saharan Africa [ ].
The pathogenesis of BL has been linked to EBV infection as a result of the isolation of the virus from cultured BL cell lines in [ 5 ]. BL occurs in children living in areas that are both holo-endemic and hyper-endemic for malaria and suggesting that Plasmodium falciparum plays a role in the etiology of the cancer [ , ].
BL is classified into three different forms based on clinical observations and disease epidemiology [ ]. Common sites of tumor occurrence of eBL are the jaws and abdomen [ ]. Sporadic Burkitt's lymphoma sBL , on the other hand, has a wide global distribution, but is at a much lower frequency and mostly diagnose in both children and young adult.
Immune compromise, which occurs as a result of HIV infection, accounts for reactivation of EBV from latently infected B cells and eventually causing rapid progression to iBL [ ]. Recent reports suggest that EBNA-1 inhibits apoptosis in BL cell lines by interacting with host proteins such as survivin, an anti-apoptotic protein and pregulator USP7 [ 38 , ]. All BL tumors, regardless of variants or EBV status, are morphologically and immunophenotypically identical and are related by sharing a general gene expression patterns which resemble that of centroblasts [ , ].
The BLs, in general, undergo chromosomal translocation of c-myc proto-oncogene on chromosome 8 or on chromosome 14 to one of the three immunoglobin loci, notably the heavy chain immunoglobin Ig [ ].
This brings the c-myc under the control of highly active Ig gene promoter leading to constitutive expression of c-myc proteins at high levels in BL cells. The expression results in uncontrolled cell growth in BL [ ]. The incidence of HL varies depending on geographical distribution, sex, ethnicity, and socioeconomic status; the incidence is higher in developed countries compared to under-developed ones. There is however lower mortality due to HL in developed countries compared to the less developed ones; an observation that has been ascribed to improved health facilities in the developed countries [ ].
There are two variants of HL based on clinical and morphological differences [ ]. Association between EBV and CHL has been suggested due to elevated antibody titres against EBV latent antigens, which proceeded the development of the lymphoma after several years of infection [ ].
Post-transplant lymphoproliferative disorder PTLD is a type of malignancy with life-threatening complications in transplant recipients of both solid organ and hematopoietic stem cell allografts [ ].
The lymphoma occurs as a result of increase proliferation of B cells after transplant, and it is mostly EBV driven [ ]. The use of immune suppressive drugs after organ transplant reduces the number and function of T cell to influence the success of the transplant.
The use of the immunosuppressant leads to depletion of EBV-specific T cells and disruption of the balance between the immune system and latent virus, and consequently, there is reactivation of EBV from latency [ ]. The impairment of EBV-specific T cell mediated immune surveillance results in uncontrolled lymphoproliferative blast, which eventually causes PTLD in transplant recipients [ , ]. These groups of people develop primary infection after receiving transplant from a donor who is EBV seropositive, predisposing them to PTLD [ , ].
The overall incidence of PTLD is found to be higher in children than in adults due to increased pretransplant EBV seronegative status among children [ ]. An alternatively simpler system of classification has been proposed which groups NPC into two histological variants, namely squamous cell carcinomas SCCs and undifferentiated carcinomas of the nasopharyngeal type UCNT [ ]. The viral infection in NPC epithelia cells is clonal in origin; developing from clonal proliferation of single EBV infected epithelia cell.
As previously mentioned, the infection of epithelia cells by EBV is mainly lytic, and hence default lytic programs are expressed. However, the switch to latency default programs during epithelia infection by EBV represents a key step in the pathogenesis of NPC, although some studies have reported the involvement of both lytic and latent stages EBV genes in transformation of epithelia cells, the role of lytic genes remains unclear [ 15 , , ].
Gastric cancer GC is the third leading cause of cancer-related mortality globally, with a worldwide annual incidence of over cases. CA-type on the other hand, morphologically resembles EBV negative GCs by infiltration of variable lymphocytes with prominent desmoplasia in the absence of lymphoid follicles [ ].
CLR-type is characterized by the presence of three or more lymphoid follicle with active germinal centers located at the advancing edge of the neoplasm [ ]. One of the unique features which distinguishes EBVaGC from non-EBVaGC is the monoclonal proliferation of gastric epithelia cells latently infected with EBV and suggesting the presence of the virus in the early stages of tumorigenesis [ ].
In contrast to EBV-negative GCs, which mainly occur in the antrum as the predominant pathological site, EBVaGC occurs predominantly in the proximal stomach including the cardia, fundus and body [ ]. At early stages of tumorigenesis, EBVaGC forms a well-defined nodular ulcer in the submucosa with less fibrosis as compared to non-EBVaGCs, and this pathological feature is essential for endoscopic submucosal resection of the tumor [ ].
The tumor is characterized by extensive angio-invasion and necrosis in the upper aerodigestive tract, including the nasal cavity, nasopharynx, paranasal sinus and the palate [ ]. The lymphoma has been shown to be predominant among men than woman, with ratio of male to female, and the mean age at diagnosis being 50 years [ , ]. In underdeveloped regions such as sub-Saharan Africa, frequency of breast cancer is relatively lower, characterized by aggressive course and targets female of younger age compared to the Western World [ ].
In keeping with the association between EBV and breast cancer, a proposed potential mechanism for the transformation of mammary epithelia cells MEC suggests that EBV infects cells that express CD21 as cell surface receptor, leading to tumorigenesis that occurs through LMP-1 mediated activation of c-MET signaling pathway [ ]. Humans are the only natural host of EBV, and the virus is transmitted by ingesting infected saliva. In the host, the virus has tropism for two main cells, namely epithelia cells and B lymphocytes, although unnatural targets such as natural killer cells and T lymphocytes have been shown to contain the virus.
The presence of EBV in B cells has been linked to lymphomas, which include Burkitt's lymphoma, Hodgkin lymphoma, and posttransplant lymphoproliferative disorders. On the other hand, infection of epithelia cells is implicated in the pathogenesis of epithelia cell derived malignancies such as nasopharyngeal cancer; EBV associated gastric cancer, and breast cancer.
The pathogenesis of both B cell and epithelia cell derived neoplasms has been due to the expression of EBV transcription programs or latency stage genes. The pathogenesis of posttransplant lymphoproliferative disorders has however been associated with the expression of latency III default programs.
Tumorigenesis occurs by 1 upregulating the expression of antiapoptotic genes, 2 constitutive activation of major intracellular signaling pathways responsible for cell growth and survival, and 3 creation of tumor microenvironment for malignant cells to escape immune recognition. EBV have been linked to the pathogenesis of different malignancies, but the mechanism underlying the pathogenesis has not been fully elucidated.
Host and environmental factors are thought to play key roles in the malignancies, making it difficult to clearly map out the mechanism involved in the pathogenesis of EBV-associated cancers.
With current progress in genomic research, future studies should focus on how host genes and environmental factors interact with viral genes, and how the interaction influences the pathogenesis of EBV-associated malignancies. Due to overlapping symptoms, many EBV implicated cancers are only diagnosed at the advance stage of the disease. Genome-wide association studies and whole genome sequencing of large population of patients are therefore recommended to identify polymorphism in genes which predisposes individuals to the above mentioned EBV-associated cancers.
Results from these studies will help identify high risk-populations for further prognostic evolution and increase the chances of detecting the cancers at early stages of development. Future studies must be done on anticancer drugs that selectively regulate the expression of EBV oncogenes involved in antiapoptosis, cell proliferation and invasion.
Finally, selective inhibition of various signaling pathways activated by EBV proteins, offers promising anticancer therapy. All the proposed recommended studies will help understand the disease mechanism, and ultimately lead to the development of therapeutic agents that will help slow down disease progression and increase survival.
Interaction of human tumor viruses with host cell surface receptors and cell entry. The extent of genetic diversity of Epstein-Barr virus and its geographic and disease patterns: a need for reappraisal. Virus research. Epstein-barr virus. Structural basis for Epstein-Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins. Nature communications.
Epstein MA. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Esau D. Viral causes of lymphoma: the history of Epstein-Barr virus and human T-lymphotropic virus 1. Virology: research and treatment.
Epstein-Barr virus-associated lymphomas. Phil Trans R Soc B. Rickinson A. Epstein-Barr Virus and its replication. Saha A, Robertson ES. Epstein-Barr virus associated B-cell lymphomas: pathogenesis and clinical outcomes.
Clinical Cancer Research. The pathogenesis of Epstein-Barr virus persistent infection. Current opinion in virology. Episomal and integrated copies of Epstein-Barr virus coexist in Burkitt lymphoma cell lines. Journal of virology. A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells.
Proceedings of the National Academy of Sciences. Kang M-S, Kieff E. Epstein-Barr virus latent genes. The interplay between Epstein-Barr virus and B lymphocytes: implications for infection, immunity, and disease. Immunologic research. The role of Epstein-Barr virus in epithelial malignancies.
The Journal of pathology. Genome-wide analysis of wild-type Epstein-Barr virus genomes derived from healthy individuals of the Genomes Project.
Genome biology and evolution. A review of human carcinogens-Part B: biological agents. The Lancet Oncology. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press. Frontiers in oncology. Characterization of the variability of Epstein-Barr virus genes in nasopharyngeal biopsies: potential predictors for carcinoma progression.
PloS one. Epstein Barr virus volume 2: one herpes virus: many diseases. Frequent presence of subtype A virus in Epstein-Barr virus-associated malignancies. Griffiths P. Distribution of Epstein-Barr virus genotypes in throat washings, sera, peripheral blood lymphocytes and in EBV positive tumor biopsies from Slovenian patients with nasopharyngeal carcinoma.
Journal of medical virology. Sequence variation in the Epstein—Barr virus latent membrane protein 1. Journal of General Virology. The Epstein-Barr virus latent membrane protein-1 LMP1 bp deletion and XhoI-polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies. Systematic reviews. World journal of surgical oncology.
Kieff E. Epstein-Barr virus and its replication. Studying viruses and cancer is helping researchers develop vaccines and other ways to reduce cancer risk. We spoke with Harrys Torres, M.
Viruses are very small organisms. There are several oncoviruses, or viruses that causes cancer:. There is currently no vaccine for Epstein-Barr virus. Hepatitis B virus HBV is spread through infected blood, semen and other body fluids. Hepatitis B is a leading cause of liver cancer. The hepatitis B vaccine is recommended for all children and adults.
Hepatitis C virus HCV is spread through infected blood. There is no vaccine against hepatitis C, but it is highly treatable. Human immunodeficiency virus HIV is spread through infected semen, vaginal fluids, blood and breast milk. It can enable other oncoviruses to cause cancer. There is no vaccine against HIV. Human herpes virus 8 HHV-8 is related to Kaposi sarcoma in people who have a weakened immune system.
That includes patients with HIV. Human papillomavirus HPV has at least 12 strains that can cause cancer in men and women, including anal, cervical, penile , throat, vaginal and vulvar cancer. Boys and girls age should get the HPV vaccine. It is spread through infected semen, vaginal fluids, blood and breast milk. The infection is rarely found in the United States. The effects of these viruses on cancer development is highly complicated.
This can cause the host cells to become cancerous. However, reactivated EBV may cause symptoms similar to those of an initial EBV infection in people who have a weakened immune system.
EBV spreads from person to person through bodily fluids, particularly saliva. But you can also get the virus by sharing personal items, such as toothbrushes or eating utensils, with someone who has an active EBV infection.
EBV can also be spread through blood and semen. You can start spreading EBV to others as soon as you contract it. This means you can pass it on to others before you even start to have symptoms of an active infection.
Once the virus becomes inactive, you can no longer spread it to others, unless it reactivates. Potential EBV infections are often diagnosed without any testing. However, blood tests can detect the presence of antibodies associated with EBV. One of these is known as the monospot test. In addition to the monospot test, there are other blood tests for more specific antibodies to EBV, including:. They can monitor you for signs of complications and give your more information about what to look for as you recover.
EBV infection can increase the risk of developing certain rare cancers. This is because mutations in cells infected with EBV can lead to cancerous changes. EBV-associated cancers are uncommon, particularly outside of Africa and some parts of Southeast Asia. Most people who have had an EBV infection will not go on to develop one of these cancers. Experts are still trying to identify these specific mutations and why EBV infection seems to cause them.
EBV may also play a role in the development of other health conditions, including autoimmune disorders and schizophrenia. EBV has long been thought to be linked to autoimmune disorders, such as lupus.
Experts believe that EBV may cause changes in the way some genes are expressed.
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