The field of tumor virology initially arose from the study of retroviruses that cause tumors in birds and mammals other than humans. The oncogenic retroviruses can be divided into three classes: (1) transducing retroviruses, (2) insertionally mutagenic retroviruses, and (3) true oncoretroviruses. Transducing retroviruses are ones that acquire genetic information from the host genome. RSV is one example. Most other examples also were isolated from avian hosts, although others have been isolated from feline, murine, and simian hosts. The cellular genetic information being transduced is a cellular proto-oncogene which, as present in and expressed from the transducing retrovirus, has oncogenic activity, i.e., it contributes to tumor formation in vivo and cellular transformation in tissue culture. The study of transducing retroviruses led to the discovery of more than a dozen oncogenes, including src, ras, and myc. The discovery of these virally encoded oncogenes, and their detailed study helped define numerous cellular signaling pathways that play fundamental roles in normal cell physiology and when altered, in carcinogenesis. It was not recognized until the 1970s that these viral oncogenes actually had been picked up by the virus from the host organism through genetic recombination, which arises as a by-product of reverse transcription. This led to the recognition that animals encode oncogenes. The cellular copies of these genes were initially referred to as proto-oncogenes because it was recognized that the viral copies of these genes had undergone genetic changes that led to the increased expression and/or activity of the encoded gene product. These changes led to the oncogenic nature of the virally transduced gene. In contrast, the cellular homologs do not contribute to cancer in their wild-type state. For example, the virally encoded src and ras genes have amino acid substitutions at positions in these proteins that lead to their constitutive activity in signal transduction pathways, and the virally encoded myc gene is missing regions of the cellular gene that normally lead to a tight regulation of its expression at the transcriptional and post-transcriptional levels. No examples of transducing retroviruses have been found for human cancers; rather, most such viruses were identified from the evaluation of laboratory stocks of retroviruses that infect laboratory animal species. Generally, these transducing, oncogenic retroviruses are replication-defective because of the disruption of one or more essential viral gene by the insertion of the cellular proto-oncogene. The rare exception is RSV, which is a replication-competent virus in which the transduced cellular src gene did not disrupt function of any viral gene. How a transducing oncogenic retrovirus arises remains unclear. It likely results from a provirus that integrates close to a cellular proto-oncogene. This could result in the formation of a chimeric RNA of viral and cellular origin which, when packaged into progeny retrovirus and on reverse transcription, undergoes recombination with a co-packaged, intact viral transcript to produce the actual transducing viral genome.

Insertionally mutagenic retroviruses are ones that, as a consequence of insertion of the proviral genome into the host chromosomes, alter the structure and/ or expression of a cellular proto-oncogene or tumor suppressor gene. These retroviruses are also known as the weakly oncogenic retroviruses since they only rarely cause cancers in laboratory animals, reflective of the low likelihood that the provirus insertion occurs at or near a cellular proto-oncogene or tumor suppressor gene. There are several mechanisms by which insertion of provirus can lead to activation of a cellular proto-oncogene. First, the virus may integrate upstream of the cellular gene in the same sense orientation such that read-through transcription from the viral promoter leads to the generation of chimeric viral:cellular mRNAs that can encode the cellular proto-oncogene. Second, the viral transcriptional enhancer can upregulate the activity of the cellular gene’s own transcriptional promoter. Finally, the virus can disrupt the integrity of the cellular mRNA leading to the loss of negative regulatory elements such as mRNA instability elements in the mRNA encoding the cellular protooncogene. Examples of each of these three cases exist in the literature. Many of the insertionally mutagenic retroviruses cause lymphomas/leukemia in their natural host. In these tumors, the provirus is found nearby to the c-myc locus, leading to increased expression of the c-myc gene product. Insertionally mutagenic retroviruses can also integrate within alleles of tumor suppressor genes and disrupt their expression, thereby leading to cancer. The identification of such events is much less frequent than those that lead to the activation of cellular proto-oncogenes, presumably because of haplosufficiency.

True oncoretroviruses are ones that, through virally encoded activities, alter the host cell or the host cell environment, thereby making cells more susceptible to cancer development. There are only a few cases of true oncoretroviruses. One is HTLV-1, which causes T-cell lymphomas in humans.

Whereas the study of RNA tumor viruses was largely responsible for the discovery of oncogenes, the study of DNA tumor viruses led to the discovery and elucidation of the function of cellular tumor suppressor genes, most notably p53 and pRb. Much of the initial knowledge about DNA tumor viruses came from the study of SV40, a simian virus. SV40 efficiently transforms cells in tissue culture and can cause tumors in hamsters, but not its natural host. Several viral gene products were found expressed in these transformed/tumorigenic cells and were identified because hamsters made antibodies against them. Most notable of these was the SV40 large tumor antigen (TAg). This protein is one of the most potent oncogenic factors known [1]. Its oncogenic activity is multifactorial, largely arising from its ability to bind and inactivate the cellular tumor-suppressor proteins p53 and pRb. p53 is now recognized to be functionally disrupted in most human cancers. The protein was originally identified by virtue of its association with SV40 TAg. Initial cloning and functional analysis of p53 led to its designation not as a tumor suppressor gene but an oncogene. This was due to the fact that the initial p53 clones were isolated from cell lines, i.e., populations of cells that had acquired an immortalized phenotype. In these cell lines the p53 gene had undergone mutations that cause the encoded gene product to possess dominant-negative activity; that is, it could inactivate the normal p53 protein when put back into cells. It was not until the late 1980s that the wild-type p53 gene was recognized to be a tumor-suppressor gene [2]. p53 is thought to play an important role in orchestrating the cellular responses to certain forms of stress, including insult from DNA-damaging agents. Activation of p53 leads either to growth arrest, which is believed to allow cells time to repair damaged DNA, or apoptosis (programmed cell death). Without functional p53, cells have a greater propensity for undergoing genetic alterations, some of which can contribute to tumorigenesis. It is now understood that when SV40 TAg binds the wild-type p53 protein, it inactivates the latter’s function [1]. SV40 TAg also can bind the gene product of the retinoblastoma tumor susceptibility locus (Rb) [3]. Rb and the related pocket proteins, p107 and p130, are critical regulators of the cell cycle. In the G1 stage of the cell cycle pRb binds to and inactivates a family of transcription factors, E2Fs, that regulate the activity of cellular genes involved in DNA synthesis and cell cycle control. Normally, pRb’s activity is regulated by cyclin-associated kinases, which phosphorylate pRb and lead to its dissociation from E2Fs. TAg upon binding to pRb or its relatives p107 and p130 can also cause this dissociation and thereby lead to cell cycle deregulation.

The insights gained from the study of SV40 provided many insights about how human papillomaviruses cause carcinoma of the anogenital tract and head/neck region in humans, and potentially also shed light on the oncogenic activities of the recently discovered Merkel cell carcinoma associated polyomavirus. However, it would be an oversimplification to think that targeting p53 and pRb are the only means by which DNA tumor viruses transform cells or cause tumors in organisms. Much like what was learnt from the study of transducing oncoretroviruses that express mutated forms of cellular proto-oncogenes, there are many varied cellular pathways targeted by DNA tumor viruses that, when altered, contribute to transformation in tissue culture and tumorigenesis in vivo.