Viruses are implicated in approximately 15% to 20% of all cancers (reviewed by Nevins, 2007; Ou and Yen, 2010). They can cause malignancies that include nasopharyngeal carcinoma, Burkitt lymphoma, cervical carcinoma, T-cell leukemia/lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, and Kaposi sarcoma. Even more importantly, oncogenes and tumor-suppressor proteins were first identified through the study of cancer-causing viruses. For example, research with simian virus 40 led to the discovery of tumor-suppressor genes, p53 and the retinoblastoma gene (Rb). Oncogenic viruses fall into 2 groups: the DNA tumor viruses that contain either linear or circular double-stranded DNA and the RNA-containing tumor viruses (also called retroviruses). DNA tumor viruses usually cause malignant transformation by inhibiting the normal function (growth control) of tumor-suppressor genes (see Chap. 7, Sec. 7.6), whereas retroviruses usually deregulate signal transduction pathways (see Chap. 8).
Stehelin et al (1976) demonstrated that Rous sarcoma virus (a retrovirus that causes sarcomas in chickens) contained nucleotide sequences that were not found in similar nontransforming retroviruses. These novel retroviral sequences, however, were closely related to nucleotide sequences present in the DNA of normal chickens. This important discovery indicated that a viral transforming gene (in this case v-src) was derived from a normal cellular gene. Many other retroviruses have been studied since and have been shown to contain different oncogenes derived from and closely related to their cellular counterparts. The normal cellular genes from which the retroviral oncogenes (v-onc) are derived are referred to as protooncogenes (or c-onc). The process by which protooncogenes become integrated into the viral genome and are converted to viral oncogenes with overt transforming activity is complex; it involves recombination between the retroviral and cellular genomes following integration of a retrovirus adjacent to a cellular protooncogene. This process, known as transduction, is accompanied by alterations in the structure and regulation of oncogene sequences. Many of the oncogenes found in transforming retroviruses have also been identified independently in spontaneously arising tumors of nonviral origin, where they appear to be activated by other mechanisms, including point mutation, gene amplification, and chromosomal translocation.
Protooncogenes encode a wide range of protein products involved in the control of cell proliferation and differentiation, including growth factors, growth factor receptors, components of signal transduction pathways, and transcription factors that regulate the synthesis of messenger RNA (mRNA). Tumor-suppressor genes, in contrast, represent genes that are likely to play a role in negatively regulating cell growth. In this chapter, the mechanisms of cellular transformation by oncogenic viruses are described. These mechanisms provide clues to more general mechanisms of transformation caused by increases in dominantly acting oncogenes or inactivation of tumor-suppressor genes.
The polyomaviruses include simian virus 40 (SV40), mouse polyomavirus, and 8 human viruses, JC virus, BK virus, KI virus, WU virus, HPyV6, HPyV7, HPyV9, and Merkel ...