Mechanisms of Viral Tumorigenesis

Molecular studies of tumor viruses in cultured cells and animals have provided important insights into many fundamental cellular processes (Nevins, 2001). These studies resulted in the discovery of mRNA splicing, transcriptional enhancers, oncogenes, and tumor suppressor proteins, and elucidated important aspects of signal transduction, immune regulation, and cell cycle control. The earliest efforts at restriction mapping and genetic engineering involved tumor viruses (Danna and Nathans, 1971; Jackson et al., 1972), and viruses were the first organisms to yield to the genomics effort (Sanger et al., 1977; Reddy et al., 1978; Fiers et al., 1978). These studies revealed that DNA tumor viruses carry their own oncogenes as essential parts of the viral genome. In contrast, most oncogenic retroviruses induce tumors under natural conditions by activating the expression of a normal cellular gene in its native chromosomal location. Retroviruses can also transform cells by transducing modified cellular genes.

Viruses have evolved to replicate their own genome and spread to new hosts, not to induce cancer. Virus-induced tumor development can thus be regarded as a biological accident or a by-product of the biochemistry of virus propagation.

In order to synthesize large amounts of viral DNA during productive infection of their host cells, most DNA viruses must first mobilize the cells to enter a state conducive to high-level DNA replication by inducing expression of proteins required for cell-cycle progression (Nevins, 2001). Thus, many DNA viruses stimulate DNA synthesis in their target cells. If lytic infection is aborted but this proliferative stimulus is sustained, growth transformation may result. For this to occur, viral genomes must persist in the infected cells, either by stable integration into the cellular DNA or by extrachromosomal DNA replication.

In the case of the HPVs (and other small DNA tumor viruses), the viral oncogene products inactivate both the Rb and the p53 tumor suppressor pathways (Nevins, 2001). Strikingly, these pathways are often crippled during the development of nonviral tumors as well. Inactivation of these tumor suppressor pathways not only provides a proliferative stimulus, but also elicits genetic instability, in part by decreasing the likelihood of growth arrest and/or apoptosis in response to DNA damage (zur Hausen, 2002). The ensuing mutations in cellular growth control genes undoubtedly play a role in further carcinogenic progression. However, despite these accumulated mutations, the proliferation of HPV-induced cervical cancer cells requires continued expression of the viral E6 and E7 oncogenes (von Knebel Doeberitz et al., 1988; Hwang et al., 1993). The mechanisms of herpesvirus transformation are more complex and appear to involve modulation of cellular signaling and cell cycle control pathways by viral proteins persistently expressed in tumor cells. In both EBV-positive (endemic) and EBV-negative (sporadic) Burkitt's lymphoma cells, the tumor is driven by the constitutive expression of the c-myc proto-oncogene activated by juxtaposition to an immunoglobulin gene by chromosomal translocation. Nevertheless, it has been reported that inhibition of the EBV-encoded EBNA1 protein can induce apoptosis in some EBV-positive Burkitt's lymphoma cell lines (Hammerschmidt and Sugden, 2004). HTLV-1 encodes an essential viral regulatory protein, Tax, which appears responsible for its transforming activity (Ross et al., 1996; Nerenberg et al., 1987). The mechanisms of hepatitis B and C virus tumorigenesis are not clear but are thought to involve repeated mutagenic cycles of liver damage and regeneration.

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