Human herpesvirus 8 (HHV-8) DNA sequences have been detected in Kaposi’s sarcoma, in primary effusion lymphoma (an unusual high-grade non-Hodgkin’s lymphoma seen primarily in patients with acquired immunodeficiency syndrome [AIDS]), and in Castleman’s disease (a rare lymphoproliferative disorder); however, proof that HHV-8 is involved in the pathogenesis of these diseases remains to be established. The alteration of the cellular genome after a carcinogenic exposure may result in malignancy if apoptosis is prevented and the immune surveillance fails to eliminate the transformed cell. Traditionally, these studies focused on gonorrhea or syphilis. Epidemiologic studies on this topic could play important roles in answering both old and new questions, which could augment current knowledge and open new areas of research. Several studies evaluate cancer risk in Africa, a region heavily affected by the HIV/AIDS epidemic. NETs from other entities, however, were negative for all HPyVs. Also important are the molecular mechanisms whereby viruses interact with the immune system and the immune evasion strategies that have evolved.
In situ hybridization indicated that mRNAs for v-cyclin D and kaposin, an HHV-8 latency-associated gene, were present in approximately 1% of the spindle cells in early patch lesions and approximately 60% of the spindle cells in late nodular lesions of Kaposi’s sarcoma. Conclusions: Spindle cells of Kaposi’s sarcoma, which have been regarded as the tumor cells of this cancer, contain v-cyclin D mRNA. According to the National Cancer Institute, Hodgkin’s lymphoma (HL) accounts for 4 − 6% of all childhood cancers, with the highest incidence rates in 15–19 year olds . Cell lines established from these secondary tumors also expressed ORF74 and were tumorigenic. There are other subtypes of childhood NHL, but they account for less than 5% of all cases. The second beta sheet in the S20-3 peptide stabilizes the loop, but at the same time, it decreases loop flexibility and increases bulkiness of the peptide, limiting its access to the K1 binding site in the presence of the K1 protein. Neuroblastoma is diagnosed in 7% of the CC cases, nephroblastoma (Wilms) tumors occurs in 5% and retinoblastoma in 3% CC cases .
Cancers found in children are usually quite distinct from those seen in adults. Because the causes of childhood cancers are unknown, it is difficult to determine a specific mechanism. Filters were washed and further incubated for 1 hour at room temperature with a 1:1000 dilution of peroxidase-conjugated anti–mouse immunoglobulin G (Sigma). In this review, we address the possible role of infectious agents in the onset and progression of childhood tumors. To date, in addition to inherited factors, the World Health Organization (WHO) classifies four different groups of external agents as carcinogens which cause cancer in children. These are physical, biological, chemical carcinogens, and dietary components (e.g., cured meats) . Antibodies against the open-reading frame 73 (LANA) were tested by a similar ELISA using full-length baculo expressed LANA as antigen and serum diluted 1 : 100.
Blood samples were taken from these two patients and added to a new Guthrie card. All serum samples were sent frozen for laboratory analysis at the Centro di Riferimento Oncologico in Aviano, Italy, where they were analysed by immunofluorescence for the presence of HHV8 antibodies by experienced laboratory personnel. In general, in 5 − 15% of CC cases genetic factors are thought to predispose the child to the development of cancer . Indeed, 10–15% of the cancers worldwide, or over 1.3 million cases of cancer each year resulting in almost a million deaths, can be linked to viral infection (Parkin, 2006). Because cancer is a multifactorial disease caused by genetic and environmental factors, it is often difficult to determine the critical period of exposure as during pregnancy or earlier . In contrast to the oncogenicity and tumorigenicity of its viral genome, KSHV infection of ECs leads to the induction of KS markers, spindle cell phenotype and signs of transformation but does not result in the acute angiogenicity and tumorigenicity characteristic of KSHV-infected spindle cells in lesions. Two models have been proposed to explain how infectious agents could play a role in the development of childhood leukemia.
The first model relies on the direct transforming ability of transforming viruses. Because HSV-1 resides in neurons during latency, cells within the brain that can mediate immune responses are key in controlling HSV infection and spread. In this case, the action of microorganisms may be indirect and non-transforming (reviewed in ). One of the main agents in the proposed infectious association with childhood leukemia is a group of human herpesviruses, especially Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). Associations of EBV with childhood leukemia, mainly lymphoblastic leukemia (ALL), have been found in some seropositivity studies, genetic analyses, and epidemiological studies. However, it is unable to bind nectin-2 but binds CD155 instead (17,–19). Epidemiological studies of HBV infection and HCC in the 1970s associated HBV with the development of HCC, and clear-cut epidemiological evidence of an etiological role was published in 1981 (29).
However the statistical significance of the results was not confirmed by a larger study of the same group . The presence of VCA antibodies is recognized as a sensitive measurement for active infection. While for EBV reactivation, testing for ZEBRA and for EBV early antigen antibody was found to be useful. In addition, ZEBRA IgG and VCA IgM antibody associations were attributed to increased risk of non-ALL in offspring. EBV ZEBRA protein interacts with mitotic chromosomes, and with p53 and promyelocytic leukemia proteins. This might suggest a proposed mechanism for the transforming activity of the virus. Recent DNA studies show that latent membrane protein 1 of the EBV gene transcripts was found in 29/80 of the cancer cases versus 0 in the control group, in cases of ALL, AML, and chronic myelogenous leukemia (CML) .
C. In the study positive controls (patients with Burkitt’s lymphoma and infectious mononucleosis) were consistently positive, but healthy donors, other disease controls, cases of AML and multiple myeloma showed negative results . There are several mechanisms by which EBV could increase the risk of malignant transformation of infected cells. We further analyzed these NETs for the presence of DNA from 12 AAVs, adeno virus-5, 27 HPVs, HBV, and XMRV. About 5% develop chronic infections, which can cause chronic active hepatitis and cirrhosis (17). Analyses of HHV-8 gene expression. Information has been reported on possible roles of HHV-6 in leukemia development (reviewed in ).
HHV-6 was first isolated from patients with lymphoproliferative disorder. In some experiments, naked DNA (10 μg) was injected intramuscularly in 0.2 ml of sterile phosphate-buffered saline (PBS) in a 25-gauge needle.  showed that HHV-6 antibody level was increased in children with ALL, but a subsequent study showed no significant difference (50 patients/50 controls). Slight but significant serological correlation was shown in case control studies with AML. The presence of HHV-6 IgM in 40% of children with leukemia, and high avidity of IgG compared with controls was shown in further studies. HHV-6 DNA was found in bone marrow cells of children with T-cell ALL. Importantly, a direct transforming ability of HHV-6 was shown in vitro with 3T3 cells and human epidermal keratinocytes.
HHV-6 also has a unique ability to integrate viral DNA into chromosomes. Chromosomal transmission of HHV-6 DNA was shown in ALL cells in culture (reviewed in ). Apart from integration into chromosomal DNA, HHV-6 protein products are also able to interfere with host protein functions. U95 binds to NF-kB, altering the pathway, and U14 and ORF-1 bind and inactivate p53 . These interactions likely contribute to the oncogenic transformation of infected host cells. The fact that neither HHV-6 DNA nor EBV were detected in dried blood spots obtained from newborns at birth indicates that congenital infections with these viruses are uncommon. Antibodies against herpes simplex, another member of the Herpesviridae, were prevalent in children with ALL in Iran.
Patients had higher values of antibodies against HSV1 IgG (82.2%) comparing to a control group of 90 age-sex matched healthy children (54.5%) . It involves sustained liver damage and inflammation by inducing a strong immunological reaction in the liver that ultimately leads to cirrhosis and cancer after several decades of chronic infection. Although association with certain infectious agents is known, analysis of the presence of exogenous genomes in leukemia cells suggests that a single transforming agent is unlikely to cause leukemia development . The mechanism for cancer development will probably involve several factors, wherein infectious agents can act as triggering factors. HL can be divided into two subtypes, EBV-associated and non-EBV-associated HL. Approximately 40 − 45% of the cases can be attributed to EBV infections, with high prevalence found in children under the age of 10 years. IL-6 and IFN-β levels were also increased following HSV-2 infection of HCE cells (Li et al., 2009).
Evidence of an associations of HL with EBV came from serological studies that showed elevated titers of anti-EBV antibodies in HL patients [39, 40]. In addition, the presence of viral DNA was demonstrated in malignant HL or Reed-Sternberg cells, where it established latency type II through the expression of Epstein-Barr nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and latent membrane protein 2A (LMP2A) proteins [40, 41]. There are three clinical variant types of BL, endemic, sporadic, and HIV-associated types. The human tumor cell lines COLO-205, NCI-H226, and BT-549 as well as the normal primary cell line HEL were included in KRAS overexpression studies. The genome of KSHV has a 140.5-kbp coding region with at least 81 ORFs (54). HIV-associated BL patients are positive for EBV in one third of all cases [41, 42]. This finding suggests that BL is a polymicrobial disease , where malaria or HIV antigens act as co-agents in BL pathogenesis .
Although mucosa-associated lymphoid tissue (MALT) NHL occurs very rarely in children, it is noteworthy that its development is also associated with infection. The presence of H. pylori is demonstrated in almost all cases of MALT lymphoma [39, 40, 45]. Approximately half of the reported pediatric MALT lymphoma cases were observed in HIV positive patients [46, 47]. Eradication of H. Reliability was high for each of these tests (κ = 1.00 for HPV-16, HPV-18, and HHV-8 infections). Nervous system tumors occur frequently in children, especially CNS tumor that is the second most common pediatric cancer.
There are many types of nervous system tumors, and they occur at different ages. Neuroblastoma can be diagnosed prenatally or during the first 3 months of life. More recently, at least eight new human polyomaviruses have been discovered (57), and one of these, MCV, was identified in patients with Merkel cell carcinoma (MCC), which is a rare but highly aggressive malignancy. v-Cyclin D transcripts detected by means of RT-PCR. Whether there is a genetic polymorphism which is crucial in a particular tumor type, or an involvement of toxins that regulate cell types at different stages of development remains unknown . The very early onset of the disease suggests that parental factors may play a role during the period prior to conception, during gestation, or at birth . DNA was digested with EcoRI and analyzed by Southern blotting, as described in Materials and Methods, with a probe consisting of the ORF74 coding region.
The infections linked to risk included rubella, mumps, varicella zoster, influenza, and herpes and respiratory infections [52, 53]. Polyomaviruses Simian virus 40 (SV40), John Cunningham virus (JCV), and BK are suspected to cause various oncological malignancies. These viruses were introduced into the human population in the 1950s  and SV40 was suspected to cause brain tumors . Later retrospective studies found no correlation of SV40 contaminated vaccines with brain cancer [56, 57]. However, later reports found that the viruses were positively correlated with CNS tumors in adults and children [58, 59]. The presence of JCV in pediatric tumors was detected by immunohistochemistry, PCR, and Southern blot, using T antigen and agnoprotein markers, but different laboratories found a discrepancy in results . In 62 cases of various pediatric CNS tumors (medulloblastoma, ependymoma, choroid plexus papilloma, and pilocytic astrocytoma) the viral DNA was found in 28% of the ependymomas, and in 20% of the choroid plexus papillomas .
In a 9-year-old patient diagnosed with pleomorphic xanthoastrocytoma, the genomic sequences of JCV LT, R, and VP1 were detected . Further cases of JCV in pediatric pleomorphic xanthoastrocytoma were not reported. A member of polyomaviruses BK is implicated in nervous system carcinogenesis. The virus is expressed in neuroblastomas, but not in normal adrenal medulla, and it colocalizes and binds to p53 . The carcinogenic mechanisms and properties of polyomaviruses (Table 1) identify them as at least acting as cofactors in carcinogenesis, especially in children who have immature immune systems. A growing number of studies on the herpes family of viruses and on childhood CNS tumors show positive correlations. Similar to EBV’s LMP-1, Tax strongly activates the NF-κB, AP-1 and CRE pathways that have a particularly potent pro-proliferative effect on lymphocytes, whereas Tax also interacts with several factors regulating chromatin remodeling, such as HDAC-1 and SWI/SNF, and causes the inhibition of DNA repair mechanisms, thus leading to genomic instability and ultimate transformation (Matsuoka and Jeang, 2007).
CMV DNA and proteins were detected in primary medulloblastoma, in cell lines, and in xenografts. Thirty-seven primary medulloblastoma cases were examined, and 34 (92%) expressed immediate-early proteins, and 27 (73%) expressed late viral proteins . The virus and viral particles were also detected in glioblastoma multiforme (GBM), a rare tumor among children . Many CMV viral proteins inhibit apoptosis in infected cells. At least six different proteins were associated with inhibition of apoptosis and could therefore enhance survival of CMV-infected tumor cells [27, 28]. It was reported that UL36 protein is responsible for chemotherapy resistance of infected cells in vitro . CMV was also found to inhibit expression of HLA class I and class II antigens and antigen presentation, and thus activation of T-cells.
CMV can also inhibit NK cell activation and cytotoxicity . At 2 days p.i., cells were fixed with methanol and stained by using Giemsa to visualize cytopathic effects (CPEs). Briefly, these are as follows: (i) the geographical distribution of viral infection should match that of cancer after adjustment for other cofactors. It is obvious that adult CNS tumors are different from childhood tumors. However, a scarcity of studies on the association of childhood nervous sytem tumors with infectious agents limits the understanding of the role of infectious agents. Therefore, studies of how and to what extent viruses, bacteria, and parasites can contribute to the development of childhood tumors are needed. There are many other types of benign and malignant tumors which occur rarely in children.
A case study of a child diagnosed with both sialoblastoma and hepatoblastoma demonstrated elevated levels of procalcitonin, proinflammatory stimulus to bacteria, and increased levels of C reactive protein, suggesting a response against bacterial infections . Sialoblastoma affects parotid glands during infancy, and is rare, with only 24 cases reported in MedLine (1990–2008). Hepatoblastoma originates in the liver, and comprises less than 1% of reported tumors among children from infancy to 3 years of age . trachomatis infection and prostate cancer. Hepatitis B virus (HBV) was found to be responsible for HCC in children in Taiwan, where HBV was endemic . This relationship of HBV and childhood cancer was established as a result of discovering 100% HBsAg seropositivity among children with HCC and HBV DNA in their neoplasms [69, 70]. The role of HBV infection in the cause of hepatocellular carcinoma is further confirmed when Taiwanese HBV immunization programme significantly reduced the cancer incidence in vaccinated children compared to non-vaccinated children .
Clearly, much research into the epidemiology, virology, and molecular biology of a virus is needed before it can be accepted as an oncovirus. DNA was extracted from the following: 1) P3HR1, an Epstein- Barr virus-infected cell line; 2) Ram, an Epstein-Barr virusinfected lymphoblastoid cell line; 3) pleural effusion cells from a patient with acquired immunodeficiency syndrome-related Kaposi’s sarcoma who had pulmonary lesions; and 4) primary effusion lymphoma cells. It accounts for 5% of all childhood cancers . Syrjanen et al. As shown in Fig. A direct oncogenic role of high risk HPV E6 and E7 proteins was identified. The viral proteins bind and thereby inactivate the tumor suppressors .
HPV probably employs the same mechanism of cancer development in different age groups, including children, and may act as an independent risk factor for oral cancer, another extremely rare childhood cancer . To continue, nasopharyngeal carcinoma (NPC) is a rare cancer which occurs on the epithelium of the nasopharynx and accounts for about 1% of all childhood tumors. According to WHO there are three subtypes of NPC, including squamous cell carcinoma commonly found in adults, non-keratinizing carcinoma, and undifferentiated carcinoma. Childhood cancer cases are usually the latter subtype and EBV is involved in its aetiology [77, 78]. It was found that abundance of LMP1 expression of EBV protein correlated with a patient’s age. There were higher levels of LMP1 in younger patients’ specimens in Tunisia (n = 22 out of 82) . It was in concordance with previous findings, where anti-viral capsid antigen, early antigen IgG and IgA levels were lower in juvenile form of NPC compared to adult form [80, 81].
NPC incidence is 1 per 100,000 children diagnosed annually in the US whilst it is more common in children of the Southeast Asia and Northern African region, with 8–25 per 100,000 cases recorded annually [82, 83]. In Hong Kong 80% of children are infected by 6 years of age and almost 100% have seroconverted by the age of 10 years . The disclosure of the EBV nuclear antigen and viral DNA in the NPC demonstrated that EBV can infect epithelial cells and is associated with their malignant transformation. Kaposi’s sarcoma (KS) is a tumor, which originates from the cell lining of lymph or blood vessels. As such, LANA can cooperate with H-Ras to transform fibroblasts (Radkov et al., 2000). Classical KS is prevalent among elderly men; whilst younger generation, located close to African equator, is prone to endemic KS, or African KS. Epidemic KS occurs in patients with AIDS caused by HIV .
It is to be noted that before the onset of HIV in 1985 KS had been endemic in Africa . It was reported that KS is caused by Human Herpes Virus 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus) in children whose immune system is weakened [87, 88]. During the period of AIDS infection the cases of childhood KS increased more than 40-fold . Prevalence of KS incidence among children is higher in Africa, where both HHV-8 and HIV are endemic, in contrast to well-resourced states, where patients have access to antiretroviral therapy [87, 90]. To sum up, the above-mentioned cancers are rare or even extremely rare in children, and more studies are needed to establish the mechanism of infection-based cancer development. However, there is still space to suspect the pathogens, which stimulate these rare malignancies in young generation. The mutation …
The other important protein in HPV carcinogenesis is E7, a phosphoprotein with two zinc fingers that shows some structural and functional similarity to adenovirus E1A and SV40 large T antigen. Various infections can also be acquired during passage through the birth canal if the mother is infected, or after admission to the nursery. It was also observed that HPV and EBV are sometimes found in breast milk and can be transmitted to the infant through breastfeeding . Some of the above mentioned viruses are also found to cause tumors in adults (i.e., HPV in the cervix and in anogenital cancers, human HHV-8 in Kaposi’s sarcoma, and EBV in Burkitt’s lymphoma). Many mechanisms are used by infectious agents to survive in a host and create favorable conditions for neoplastic transformation. It is also possible that a child can inherit mutations that occurred in the germ cells of the parents via viral mutagenesis. Partial sequences of HHV-6A have been found in members of the same families .
All of the mechanisms listed in Table 1 could be exploited in combination, synergistically creating favorable conditions for neoplastic lesions to develop. Disruption of tumor suppression, in combination with apoptosis, immune evasion, and low-grade inflammation could enhance the accumulation of mutations, and this would select for preneoplastic cells, which over time could lead to the development of a tumor. Infants are born with an undeveloped immune system, and the prevalence of latent viral infections in adults that come in contact with newborns could facilitate the transmission of viruses. Thus, the chance of latent infections is likely. There are several proposed theories for childhood cancer development. Thus, the high-risk HPVs are powerful human cancer viruses that express oncoproteins that act at multiple stages in tumorigenesis from events involved in tumor initiation to later stages of tumor promotion. Therefore, this pattern of restricted HHV-8 gene expression in the majority of Kaposi’s sarcoma spindle cells provides additional support favoring a latent mode of HHV-8 infection in Kaposi’s sarcoma lesions.
It states that a child’s immature immune system requires early exposure to common infections for the proper immune system maturation. The lack of it leads to the aberrant response to infection. 3B, lane 4), or tissue from a normal mouse (Fig. they had aberrant response to delayed exposure to infectious agents . Another hypothesis, the Kinlen hypothesis, proposes that a common infectious agent is responsible for increased leukemia cases transmitted by adults during a large-scale rural–urban population mixing . Both Greaves and Kinlen hypothesis are supported by epidemiological data which accumulated over the past 15 years. They propose an unknown infectious agent (mostly viral by Kinlen) that trigger an aberrant immune response and thus can be a causative agent of childhood ALL.
A more recent unifying hypothesis, of “cell transformation by replication-defective mutants,” suggests that only viruses which have defects in replication machinery show elevated transformation potential, and when they are present in cells with certain chromosomal translocations, it can lead to leukemia development . Finally, the “infective lymphoid recovery” hypothesis proposes that infective stress, triggering the heat shock response in infancy, stimulates proinflammatory cytokines and inhibits apoptosis. This, in turn, leads to a decline in antitumor immunity and in B-cell maturation arrest. This hypothesis addresses the infection paradox stated in Greaves’ and Kinlen’s hypotheses, that an unhygienic environment primes the adaptive immune response and is protective against childhood ALL, while multiple infections occurring later increase the risk of childhood ALL . Overall, it is proposed that infection can be a triggering mechanism, and most likely, the immunological state, genetic alterations, and infections have a cumulative effect on leukemia development, and possibly on the development of other cancer types.