Tumour virology--history, status and future challenges.

Viruses enter host cells in order to complete their life cycles and have evolved to exploit host cell structures, regulatory factors and mechanisms. The virus and host cell interactions have consequences at multiple levels, spanning from evolution through disease to models and tools for scientific discovery and treatment. Virus-induced human cancers arise after a long duration of time and are monoclonal or oligoclonal in origin. Cancer is therefore a side effect rather than an essential part of viral infections in humans. Still, 15-20% of all human cancers are caused by viruses. A review of tumour virology shows its close integration in cancer research. Viral tools and experimental models have been indispensible for the progress of molecular biology. In particular, retroviruses and DNA tumour viruses have played major roles in our present understanding of the molecular biology of both viruses and the host. Recently, additional complex relationships due to virus and host co-evolution have appeared and may lead to a further understanding of the overall regulation of gene expression programmes in cancer.

Perspectives in studies of human tumor viruses.

Tumor viruses can be found in both the RNA and DNA virus kingdoms. All RNA tumor viruses belong to the retrovirus family. Directly transforming Class I RNA tumor viruses carry cellular oncogenes, picked up by accidental recombination, and usually selected for secondary modifications and high tumorigenicity by the investigator. They are not known to play any role for tumor causation in nature. Class II or chronic RNA tumor viruses do not carry cell-derived oncogenes but they often act by proviral DNA insertion into the immediate neighborhood of a cellular oncogene. Feline, murine, and avian leukemia viruses belong to this category. The human adult T-cell leukemia virus, (HTLV-1) and bovine leukemia virus (BLV) act by expanding the preneoplastic cell population and thereby provides the soil for secondary, cellular changes. The DNA tumor viruses belong to three very different categories, the papovaviruses, adenoviruses and herpesviruses. Inactivation of the Rb and the p53 pathway by the viral transforming proteins is a convergent feature of the papova- and the adenoviruses. Since all DNA tumor viruses kill their host cell following their entry into the lytic phase, transformation and tumorigenicity are entirely dependent on a non-lytic interaction. Cells transformed by DNA tumor viruses depend on the continued expression of the virally encoded oncogene. They provide thereby a convenient target for the immune surveillance of the host. Depending on the epidemiological history of the virus in relation to its natural host species, the immune surveillance of the host and the strategy of viral latency and survival can evolve into a truly symbiotic relationship, as best illustrated by the Epstein-Barr virus (EBV). Tumor development occurs only as an accident at the level of the host (immunosuppression) or the cell (specific translocations or other genetic changes). The list of human viruses presently known to cause or to contribute to tumor development comprise four DNA viruses, namely Epstein-Barr virus, certain human papilloma viruses subtypes, hepatitis B virus, and Kaposi sarcoma herpesvirus (HHV-8); and two RNA viruses, adult T-cell leukemia virus (HTLV-1) and hepatitis virus C.

Kaposi's sarcoma-associated herpesvirus: a new DNA tumor virus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly identified gammaherpesvirus associated with all clinical forms of Kaposi's sarcoma (KS), body-cavity-based, primary effusion lymphomas (PELs), and a subset of Castleman's disease (CD). Sequence analysis of the KSHV genome demonstrates an extensive array of genes with homology to cellular genes involved in cell cycle regulation, cell proliferation, apoptosis, and immune modulation. Functional studies indicate that these genes may modify the host cell environment, contributing to the pathogenesis of KSHV-associated disorders. Several KSHV genes have been found to cause dysregulated cell proliferation or to interfere with established tumor suppressor pathways. The epidemiologic association of KSHV with malignancies and the coding features of its genome suggest that it is a new DNA tumor virus.

Constructing immortalized human cell lines.

Obtaining an abundant supply of human cells with specific differentiated properties is a key issue in many research studies and biotechnology applications. Recent advances in this area include the finding that forced expression of the enzyme telomerase can greatly increase the proliferative potential of at least some types of human cells, and also the development of methods for culturing human stem cells.

Oncogenes and tumour-suppressor genes in squamous cell carcinoma of the head and neck.

Cancer is now considered to be a multi-hit process which involves a number of aberrant genetic events culminating in malignant transformation. In squamous cell carcinoma (SCC) of the head and neck the action of both oncogenes and tumour-suppressor genes has been identified during the course of the disease. Cytogenetic analysis of these carcinomas has demonstrated chromosomal breakpoints, particularly in the regions of 1p22 and 11q13 together with frequent amplification of the proto-oncogenes in the 11q13 amplicon; int-2, hst-1 and bcl-1. Ras mutations have been infrequently identified in the Western World whereas ras over-expression has been a common finding and may be associated with the early development of head and neck cancer. C-myc over-expression appears to correlate with a poor prognosis for these patients. The tumour-suppressor gene p53 is also thought to be involved in the development of SCC in head and neck tumours and its aberrant expression is associated with a history of heavy smoking and heavy drinking. E-cadherin, a putative tumour-suppressor gene is down-regulated in poorly differentiated head and neck SCC and maybe important in nodal metastasis. A recent study has indicated that the Human Papilloma Virus (HPV 16 and 33) has a role in the aetiology of tonsillar carcinomas and HPV has been shown to produce transforming proteins which bind to and inactivate the p53 tumour suppressor gene. This evidence suggests that the possibility of a viral mechanism for the development of SCC in the head and neck should be considered. This paper proposes a series of genetic events to explain the development of SCC of the head and neck.

[Can virus cause oral cancers?]. / Kan virus forårsake kreft i munnhulen?

Tumour viruses are thought to contribute to the development of one fifth of all human cancers, although the mechanisms involved are still obscure. Human papilloma virus (HPV) is a DNA virus associated with oral carcinomas. It has been shown that virus DNA has to become integrated into cellular DNA in order to transform normal to malignant cells. Cellular oncogenes and tumour suppressor genes are potential cancer genes. They are involved in the control of growth and differentiation of normal cells. It is known that structural or regulatory changes (activation) of these genes will lead to malignant transformation. Virus integration will sometimes take place in close relation to cellular oncogenes. Such incorporation may result in oncogene activation. Other cellular factors that may contribute to the development of oral squamous cell carcinoma are also discussed.

Some aspects of the role of viruses in cancer.

The cells of tumours induced by many oncogenic DNA viruses, or cells transformed in vitro, contain virus-specific T and transplantation antigens; these have been described for SV40 virus, polyoma virus and adenoviruses. The investigation of viruses as causes of malignant disease in man has sought to establish whether tumour cells possess these virus-specific proteins; however, to date and with the limitations of present techniques, this enquiry has not demonstrated the above viruses as causal of human cancer. More recent studies with herpesvirus type 2 (HSV-2) have shown this virus to transform animal and human cells in culture, and induce cancer in experimental animals: for these reasons, many researchers have suggested that this agent may be an agent of some forms of cancer, in particular carcinoma of the cervix. The possible association of HSV-2 with human malignant disease is discussed.