In carcinomas, many epithelial cells undergo an epithelial-mesenchymal transformation. Transformed cells often exhibit chromosomal aberrations and the changes seen in transformation often, but not always, result from the integration of the viral genome into the host cell's chromosomes. This foreign gene can be carried into a cell by the virus and cause the host cell to take on new properties. The discovery of viral oncogenes in retroviruses led to the finding that they are not unique to viruses and homologous genes called proto-oncogenes are found in all cells.
Indeed, it is likely that the virus picked up a cellular gene during its evolution and this gene has subsequently become altered. Normally, the cellular proto-oncogenes are not expressed in a quiescent cell since they are involved in growth which is not occurring in most cells of the body and development; or they are expressed under strict control by the cell. However, they may become aberrantly expressed when the cell is infected by tumor viruses that do not themselves carry a viral oncogene.
We shall see later how this happens but it is clear that a virus may cause cancer in two ways: It may carry an oncogene into a cell or it may activate a cellular proto-oncogene. The discovery of cellular oncogenes opened the way to the elucidation of mechanisms by which non-virally induced cancers may be caused. We shall investigate what the protein products of the viral and cellular oncogenes do in the infected cell and in cells in which cellular proto-oncogenes are expressed. We shall see that their functions strongly suggest mechanisms by which cells may be transformed to a neoplastic phenotype.
The discovery of cellular oncogenes led to the discovery of another class of cellular genes, the tumor repressor suppressor genes or anti-oncogenes. Initially, the involvement of viral and cellular oncogenes in tumors caused by retroviruses was much more apparent than the involvement of the DNA tumor virus oncogenes but the discovery of tumor repressor genes as a result of our knowledge of how retroviruses cause cancer led to the elucidation of the mode of action of DNA virus oncogenes.
It should be noted that while retroviruses have been instrumental in elucidation of the mechanisms of oncogenesis, most human cancers are probably not the result of a retroviral infection although retroviruses are important in cancers in some animals. It is becoming much more apparent that many human tumors may result from infection by DNA tumor viruses. They have two life-styles:. Papilloma virus Computer colorized EM image. All 72 capsomeres are pentamers of the major structural protein.
Copyright Dr Linda M Stannard , used with permission. Figure 3A Venereal warts in the anal region of the perineum. The first DNA tumor viruses to be discovered were rabbit fibroma virus and Shope papilloma virus, both discovered by Richard Shope in the s. Papillomas are benign growths, such as warts, of epithelial cells. They were discovered by making a filtered extract of a tumor from a wild rabbit and injecting the filtrate into another rabbit in which a benign papilloma grew.
However, when the filtrate was injected into a domestic rabbit, the result was a carcinoma , that is a malignant growth. A seminal observation was that it was no longer possible to isolate infectious virus from the malignant growth. This was because the virus had become integrated into the chromosomes of the malignant cells.
The Papillomaviridae were formerly classified with the Polyomaviridae within the family Papovaviridae so named for Pa: papilloma; Po: polyoma; Va: vacuolating. This term is no longer used, the papillomas and polyomas now being considered separate families.
The papillomaviridae are small non-enveloped icosahedral DNA viruses figure 2. The major capsid protein, L1, is present as 72 pentamers capsomers.
This protein is all that is required to form the icosahedral capsid which occurs by self assembly. Each pentamer is associated with one molecule of another minor capsid protein, either L2 or L3. Papilloma viruses have a genome size about 8 kilobases and t he DNA is complexed with histone proteins encoded by the host cell. These viruses cause warts figure 3A and also human and animal cancers.
Warts are usually benign but can convert to malignant carcinomas. This occurs in patients with epidermodysplasia verruciformis figure 3B. E pidermodysplasia verruciformis is also known as Lewandowsky-Lutz dysplasia or Lutz-Lewandowsky epidermodysplasia verruciformis and is very rare. It is an autosomal recessive mutation that leads to abnormal, uncontrolled papilloma virus replication. This results in the growth of scaly macules and papules on many parts of the body but especially on the hands and feet.
E pidermodysplasia verruciformis, which is associated with a high risk of skin carcinoma , is typically associated with HPV types 5 and 8 but other types may also be involved. Papilloma viruses are also found associated with human penile, uterine, cervical and anal carcinomas and are very likely to be their cause; moreover, genital warts can convert to carcinomas. Squamous cell carcinomas of larynx, esophagus and lung appear very like cervical carcinoma histologically and these may also involve papilloma viruses.
Recently , a strong causal link between certain oral-pharyngeal cancers and HPV16 has been demonstrated. Epidermodysplasia verruciformis. This widespread, markedly pruritic, erythematous eruption was eventually found to be caused by human papillomavirus infection. Verrucous carcinoma. The epithelium shows surface maturation, parakeratosis, and hyperkeratosis. There is little or no cellular atypia. The stroma shows a mild chronic inflammatory infiltrate.
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These studies have contributed to the identification and functional understanding of a number of mammalian cell DNA replication factors. In addition, studies of SV40 large T-antigen led to the identification of protein nuclear localization and trafficking sequences Kalderon et al.
Major contributions to understanding the nature of in vivo protein degradation and the ubiquitin pathway came from studies of the high risk HPVs associated with human cancer. Studies with the E6 and p53 led to the identification p53 as the first mammalian substrate of the ubiquitin-dependent polypeptide degradation system Scheffner et al.
Subsequent studies, including those with the adenoviruses Querido et al. Certain small DNA tumor viruses cause disease in man. Specifically using non-stringent hybridization conditions, he and his colleagues identified two new HPV types HPV16 and HPV18 in cervical cancer specimens and demonstrated their association with carcinomas and precancerous lesions of the cervix Boshart et al.
Another subset of HPV the beta genus , members of which were first identified and studied by Gerard Orth and Stephania Jablonska in patients with epidermodysplasia verruciformis Orth, , may also have a role in skin cancers.
If they are etiologic agents in these cancers, their role may involve a hit and run mechanism, since the viral DNAs are not generally found in these tumors. Although SV40 and the human polyomaviruses have been important models for studying cellular transformation, their potential role in human cancers has been less clear. There have been periodic reports dating back to the s claiming the presence of SV40 DNA in a variety of different human cancers, including osteosarcomas, mesotheliomas, pancreatic tumors and brain tumors.
This has been a very controversial area and one that has received considerable scrutiny from investigators in the field and by the National Cancer Institute Poulin and DeCaprio, ; Shah, The recent identification of a new human polyomavirus in Merkel cell cancers, however, appears to be a solid candidate for behaving as a human cancer virus Feng et al.
Methods such a single DNA molecule sequencing and high density SNP arrays for readily detecting very small amounts of viral DNA integrated into host cell genomes now exist. With their application to searches for new DNA tumor viruses in human tumors, other new, small DNA human tumor- associated viruses might be discovered in the years ahead. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.
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Fax: E-mail: ude. Copyright notice. The publisher's final edited version of this article is available at Virology. See other articles in PMC that cite the published article. Abstract Studies of the small DNA tumor viruses the polyomaviruses, the adenoviruses and the papillomaviruses have led to fundamental discoveries that have advanced our understanding of basic mammalian cell molecular biology processes such as transcription and DNA replication, uncovered pathways and genes often perturbed in human cancer, and identified bona fide human cancer viruses.
Open in a separate window. In vivo sequence requirements of the SV40 early promotor region. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer.
EMBO J. Polyoma virus transforming protein associates with the product of the c-src cellular gene. Studies of simian virus 40 DNA. A cleavage map of the SV40 genome. J Mol Biol. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene.
A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. The regulation of E2F by pRB-family proteins. They presented their findings at the annual meeting of the American Association for Cancer Research. Approximately 10 percent of cases occur in non-smokers.
It's not clear how HPV reaches the lung, she says; patients may simply breathe it in. And just because these patients have evidence of an HPV infection that does not necessarily mean the infection caused their tumors, Mehra cautions. Although the majority of people are exposed to HPV, these results are largely not cause for concern, assures Mehra. Some fear that they are 'contagious', and could somehow pass the cancer onto their families," she says. And people who have lung cancer but never smoked need not rush to their doctors to determine if they also have HPV, since doctors don't know yet if they should treat these tumors differently, or if the presence of the virus has any impact on prognosis.
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