Viral Carcinogens

Dr.Ahmad

Viral Carcinogens



One of the first observations that cancer may be caused by transmissible agents was by Peyton Rous in 1911 when he demonstrated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts. 136 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus (RSV). At present, several human viruses are known to have oncogenic properties, and several have been causally linked to human cancers (Table 9-10). 137 It is estimated that 15% of all human tumors worldwide are caused by viruses

aBased on information in the International Agency for Research on Cancer Monographs. 137

bOnly tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower frequency or with insufficient data to prove causality.

[FONT=&quot]Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle checkpoints or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retroviruses and contain a reverse transcriptase. After the viral infection, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent, thus integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry oncogenes derived from cellular genes. These cellular genes, referred to as protooncogenes, usually are involved in mitogenic signaling and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 9-11)[/FONT]

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Integration of the provirus upstream of a protooncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorporation of the cellular gene into the viral genome. 138 On the other hand, many retroviruses do not possess oncogenes, but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular protooncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence.

Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular in origin. These genes are required for viral replication utilizing the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, leading to cell death and the release of newly formed viruses. In nonpermissive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, leading to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellular tumor suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, while others target different cellular proteins. DNA viruses have been shown to transactivate several cellular genes, including IL-6, c-myc, c-jun, c-fos, c-H-ras, inducible nitric oxide synthase, AP-1, AP-2, NF-[IMG]file:///C:/DOCUME%7E1/Family/LOCALS%7E1/Temp/msohtmlclip1/01/clip_image001.gif[/IMG]B, and SP1. 139

Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two, rather than one, cellular oncogenes in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, 138 emphasizing the cooperation between transforming genes. Furthermore, some viruses encode genes that suppress or delay apoptosis, such as the adenovirus E1B-19K protein that is functionally similar to the Bcl-2 family of antiapoptotic proteins, 138,140 which may also play a critical role in transformation.

Although immunocompromised individuals are at elevated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs several years after the viral infection. It is estimated, for example, that the risk of hepatocelluar carcinoma among hepatitis C virus–infected individuals is 1 to 3% after 30 years. 141 There may be synergy between various environmental factors and viruses in carcinogenesis. Factors that predispose to hepatocellular carcinoma among hepatitis C virus–infected patients include heavy alcohol intake, hepatitis B co-infection, and possibly diabetes






source : Schwartz's Surgery 8e

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[align=center]Thanx very much
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