It is estimated that viral infections contribute to 15-20% of all human cancers (McLaughlin-Drubin et al, 2008, p127). Over the past 30 years it has become much more evident that there are several viruses that keep showing up in cancerous tissues and it is becoming more evident that these viruses play a large role in the multistage development of this 15-20% of human cancers (McLaughlin-Drubin et al, 2008, p127).According to (Fey et al 1998, p2) viruses are associated with about 20% off female and slightly less than 10% of male cancer incidence worldwide. Some of the foremost cancer causing viruses in humans are oncogenic (promotes the cause of cancers) viruses which can contribute to different steps of the carcinogenic process (McLaughlin-Drubin et al, 2008, p127). These viruses include papillomavirus, hepatitis B virus, hepatitis C virus and Epstein-Barr virus which appear to be related to certain human cancers such as cervical carcinoma, primary liver cell carcinoma (Hepatocellular carcinoma), Burkitt's lymphoma and nasopharyngeal carcinoma and many others. (Fey et al 1998, p1). One of the main pieces of evidence that shows viruses cause, or at least contribute to cancer includes the presence of viral DNA, RNA and proteins in tumours (Fey et al 1998, p1).
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The ability to fuse cells is shared by many enveloped viruses. Some of these viruses include common human pathogens and most of the known oncogenic viruses. These viruses enter cells with the help of viral proteins that fuse cell membranes (Marsh et al,2006, p729). A well-known consequence of this mechanism is the ability of viruses, including common human pathogens and several viruses to fuse cells, both in vitro and in vivo (D.M. Duelli et al, 2007, p431). Viruses that can fuse cells are nearly anywhere within humans suggesting that accidental fusion in the body is not uncommon (Duelli et al, 2007, p431). Normally this is not harmful but cells made by accidental fusion are likely to be abnormal. This could potentially lead to chromosomal instability which underlies most malignant properties of many cancers and their ability to escape treatment, a virus causes cancer by inducing massive chromosomal instability through cell fusion (Duelli and Lazebnik, 2007, p968). In other words, when the enveloped virus enters a cell one of the mechanisms it can use is cell membrane fusion. The virus does this by attaching it's envelope to the surface membrane of the cell with external glycoproteins. Once attached the envelope then unfolds and releases its genetic material into the cell and the envelope itself becomes part of the cell membrane, as seen in Figure 1. The genetic material then "chops and changes" the host cell's genome to help suit its requirements for replication (Eckert et al, 2001, p778); this is not the only way a virus can gain entry to a cell. As previously stated, this change in genetic information can lead to chromosomal instability and can then potentially lead to carcinogenesis, this can be caused by both DNA and RNA tumour causing viruses. This being said does not mean that viruses alone cause cancer. Some other factors which affect the progression from viral infection to cancer include the immune system, irradiation, mutation, the presence of other viruses or carcinogens and treatment. These factors along with the chromosomal instability caused by the virus in question may cause cancer.
RNA tumour viruses:
RNA tumour causing viruses are one of the two classes of tumour virus, also known as "Oncornaviruses" (Temin, 1971, p609) contain an RNA genome and a DNA polymerase. They also typically create oncogenes which can cause cancer in their hosts.RNA tumour viruses have been isolated from reptiles, birds, and many other kinds mammals, including primates. However, none have been isolated from humans, although humans can become infected by them (Temin, 1974, p155).
Hepatitis C is an example of a single-stranded RNA virus that has a link with carcinogenesis. According to the World Health Organization (WHO), cirrhosis and primary liver cancer caused 783,000 and 619,000 deaths in 2002 (Perz et al, 2006, p519)." Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, perhaps even the most common" according to Beasley (2006, p1942). Hepatocellular carcinoma contributes to 70% to 85% of all cases of liver cancer (Perz et al, 2006). Chronic infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) is associated with a higher risk of developing HCC. A recent study of this in 2002 has shown that HBV- and HCV are accountable for 54% and 31% of HCC (Perz et al, 2006, p534). In the majority of infected individuals, HCV establishes a persistent and life-long infection by evading the immune system by mutation, preventing its host cells from apoptosis and interfering with cellular functions (Gale et al, (2005. p940). Infection with HCV causes inflammation and fibrosis of the liver, which in the later stages can progress to cirrhosis and ultimately lead to tumour development (McLaughlin-Drubin et al, 2008, p132). While it is currently thought that chronic inflammation and cirrhosis play key roles in HCV-induced carcinogenesis, the exact underlying mechanisms are not fully understood (Fattovich et al, 2004, p35). However this does not mean the mechanisms are not understood at all. It has been found that proteins encoded by HCV have also been shown to activate cellular oncoproteins and create oncogenes, such as p53, CREB2/LZIP and the retinoblastoma protein (pRB). Finally, HCV causes genome instability, suggesting that certain HCV proteins may have a cause mutation by manipulating the host cells genetic information (McLaughlin-Drubin et al, 2008, p132). So even though the underlying mechanisms are not fully understood there is still research to be done on these HCV proteins which could reveal the accurate role of HCV in carcinogenesis.
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DNA tumour viruses
Certain DNA tumour viruses, such as human papillomavirus (HPV), Epstein-Barr virus (EBV) and hepatitis B virus (HBV) cause cancers in their host cells, whereas other DNA tumour viruses, such as human adenoviruses, can transform cultured cells and only cause tumours in heterologous animal models(McLaughlin-Drubin et al, 2008, p129). Unlike RNA tumour causing viruses DNA viruses are more likely to encode proteins which deactivate tumour suppressors. This is not the only mechanism that DNA virus have that can cause cancer though; DNA tumour viruses can also create oncogenes.
Unlike hepatitis C virus, hepatitis B virus is an example of a small DNA virus with circular, partially double-stranded, DNA genome which also has a link with carcinogenesis. Also like hepatitis C, infection with HBV can enter a cell and can cause changes to the host cells genome such as chromosomal deletions and replacing the cells genetic material with its own viral sequences from one chromosome to another (McLaughlin-Drubin et al, 2008, p132), this may case genomic instability and could also activate proto-oncogenes (normal forms of oncogenes are called proto-oncogenes) (Zhen-Liang Qu, 2005, p5631) which could cause carcinogenesis. Upon examination of the DNA sequences present in HCC, proteins encoded by HBV can be seen that. These DNA sequences show the encoding of the HBV X protein (HBx) and truncated envelope PreS2/S viral proteins seem to be present in the majority of HCC tumour cells. Also viral hepatitis B spliced protein (HBSP) has been identified in HBV-infected patients (Soussan et al, 2000, p57). HBx has been reported to interact with several different cellular proteins, including binding to XAP-1, the human homolog of the simian repair protein UVDDB. The normal function of XAP-1/UVDDB is thought to involve binding to damaged DNA; this interaction may affect the cell's capacity to correct errors in the genome. In a study conducted by Becker (1998, p266) it was found that HBx does in fact prevent the cell from efficiently repairing damaged DNA, thus leading to an accumulation of DNA mutations and, eventually, cancer. The presence of the viral proteins PreS2/S and HBSP and in tumours does not confirm their role or the role of hepatitis B in HCC development therefore further studies on these proteins is necessary to determine their potential contributions to HCC development.
Epstein-Barr virus (EBV) is a herpesvirus and is a double-stranded DNA virus and was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the world's population according to Thompson et al (2004, p 803). Although most humans live with the virus without serious problems only a small amount of people from the infected population develop tumours.Â All phases of the EBV life cycle are associated with human disease according to McLaughlin-Drubin et al ( 2008, p135). It is the only virus that has been so far discovered to be consistently associated with certain malignant tumours in especially in Burkitt's lymphoma and Hodgkin's Disease according to Nonoyama et al (1973, p3265). The association of Epstein-Barr virus has also been found in nasopharyngeal carcinoma (Nonoyama et al, 1973, p3265). EBV-associated malignancies occur in high frequency in distinctive geographical locations and racial groups, indicating that the hosts genetic factors may influence the disease risk according to McLaughlin-Drubin et al ( 2008, p135). To be oncogenic, EBV must maintain its viral genome in the cell, avoid killing the cell, and prevent the cell from becoming a target for destruction by the immune system (Thompson et al, 2004, p 811).Â EBV does this by infecting and replicating in the oral epithelium and integrating its viral DNA into the host genome of infected B-cells and in certain circumstances even infecting T-cells and natural killer cells (NK cells). EBV establishes latent infection in B lymphocytes (lymphocytes are a type of white blood cell along with T cells and NK cells) and therefore the virus ensures transmission to cell progeny when B lymphocytes replicate. (Thompson et al, 2004, p 811). Its presence in the various stages of B-cell development, and its ability to infect certain epithelial cells, can have pathogenic consequences, and can contribute to the development of a various lymphomas and carcinomas (Pattle et al, 2006, p1193). EBV encodes several viral proteins that have the potential to create oncogenes, including EBV latent membrane protein 1 and 2 (LMP1 and LMP2) and EBV nuclear antigen 1, 2 and 3 (EBNA1, EBNA2 and EBNA3). These proteins help EBV achieve latency and enable cell survival by preventing apoptosis (the cells ability to "commit suicide" when infected) and because cytotoxic responses to EBNA-1 are rare, EBNA-1-expressing lymphocytes escape immune surveillance (Thompson et al, 2004, p 811).
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