Oncogene virus

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Understanding the origin of retroviral oncogenes raised the question as to whether non-virus-induced tumors contain cellular oncogenes that were generated from proto-oncogenes by mutations or DNA rearrangements during tumor development. Direct evidence for the involvement of cellular oncogenes in human tumors was first obtained by gene transfer experiments in the laboratories of Robert Weinberg and of the author in DNA of a human bladder carcinoma was found to efficiently induce transformation of recipient mouse cells in culture, indicating that the human tumor contained a biologically active cellular oncogene Figure Both gene transfer assays and alternative experimental approaches have since led to the detection of active cellular oncogenes in human tumors of many different types Table Detection of a human tumor oncogene by gene transfer.

DNA extracted from a human bladder carcinoma induced transformation of recipient mouse cells in culture. Transformation resulted from integration and expression of an oncogene derived from the human more Some of the oncogenes identified in human tumors are cellular homologs of oncogenes that were previously characterized in retroviruses, whereas others are new oncogenes first discovered in human cancers. The first human oncogene identified in gene transfer assays was subsequently identified as the human homolog of the ras H oncogene of Harvey sarcoma virus see Table Three closely related members of the ras gene family ras H, ras K, and ras N are the oncogenes most frequently encountered in human tumors.

The ras oncogenes are not present in normal cells; rather, they are generated in tumor cells as a consequence of mutations that occur during tumor development. The ras oncogenes differ from their proto-oncogenes by point mutations resulting in single amino acid substitutions at critical positions. The first such mutation discovered was the substitution of valine for glycine at position 12 Figure Other amino acid substitutions at position 12, as well as at positions 13 and 61, are also frequently encountered in ras oncogenes in human tumors.

In animal models, it has been shown that mutations that convert ras proto-oncogenes to oncogenes are caused by chemical carcinogens, providing a direct link between the mutagenic action of carcinogens and cell transformation. Point mutations in ras oncogenes. As discussed in Chapter 13, the ras genes encode guanine - nucleotide binding proteins that function in transduction of mitogenic signals from a variety of growth factor receptors. The mutations characteristic of ras oncogenes have the effect of maintaining the Ras proteins constitutively in the active GTP-bound conformation.

Because of the resulting decrease in their intracellular GTPase activity, the oncogenic Ras proteins remain in the active GTP-bound state and drive unregulated cell proliferation. Point mutations are only one of the ways in which proto-oncogenes are converted to oncogenes in human tumors. Many cancer cells display abnormalities in chromosome structure, including translocations, duplications, and deletions.

The gene rearrangements resulting from chromosome translocations frequently lead to the generation of oncogenes. In some cases, analysis of these rearrangements has implicated already known oncogenes in tumor development. In other cases, novel oncogenes have been discovered by molecular cloning and analysis of rearranged DNA sequences.

The first characterized example of oncogene activation by chromosome translocation was the involvement of the c- myc oncogene in human Burkitt's lymphomas and mouse plasmacytomas, which are malignancies of antibody -producing B lymphocytes Figure Both of these tumors are characterized by chromosome translocations involving the genes that encode immunoglobulins.

The fact that the immunoglobulin genes are actively expressed in these tumors suggested that the translocations activate a proto-oncogene from chromosome 8 by inserting it into the immunoglobulin loci. This possibility was investigated by analysis of tumor DNAs with probes for known oncogenes, leading to the finding that the c- myc proto-oncogene was the chromosome 8 translocation break point in Burkitt's lymphomas.

These translocations inserted c- myc into an immunoglobulin locus, where it was expressed in an unregulated manner. Such uncontrolled expression of the c- myc gene, which encodes a transcription factor normally induced in response to growth factor stimulation, is sufficient to drive cell proliferation and contribute to tumor development.

Translocation of c- myc. The c- myc proto-oncogene is translocated from chromosome 8 to the immunoglobulin heavy-chain locus IgH on chromosome 14 in Burkitt's lymphomas, re-sulting in abnormal c- myc expression.

Translocations of other proto-oncogenes frequently result in rearrangements of coding sequences, leading to the formation of abnormal gene products. The prototype is translocation of the abl proto-oncogene from chromosome 9 to chromosome 22 in chronic myelogenous leukemia Figure This translocation leads to fusion of abl with its translocation partner, a gene called bcr , on chromosome The fusion of Bcr sequences results in unregulated activity of the Abl protein-tyrosine kinase , leading to cell transformation.

Translocation of abl. The abl oncogene is translocated from chromosome 9 to chromosome 22, forming the Philadelphia chromosome in chronic myelogenous leukemias. The abl proto-oncogene, which contains two alternative first exons 1A and 1B , is joined more A distinct mechanism by which oncogenes are activated in human tumors is gene amplification , which results in elevated gene expression. Gene amplification see Figure 5.

The six major human oncoviruses are able to target many of these pathways. Natural barriers to viral oncogenesis are the immune response and the innate safeguard for human cancer constituted by the multi-hit nature of the carcinogenesis process, for which viral infection contributes only partially.

Environmental and host co-factors such as immunosuppression, genetic predisposition or mutagens can each affect this delicate equilibrium and could accelerate the development of these cancers. The infectious nature and long incubation periods of human viral cancers provide unique windows of opportunity for prevention and clinical intervention. We thank Drs.

Douglas Hanahan and Robert Weinberg for developing this insightful concept of cancer development. It constitutes the inspiration and conceptual framework of this review. We also thank our colleagues for their contributions to our understanding of virally induced cancers.

We regret that for space reasons we were not able to comprehensively reference all their contributions. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Cell Host Microbe. Author manuscript; available in PMC Mar Enrique A. Mesri , 1 Mark Feitelson , 2 and Karl Munger 3. Author information Copyright and License information Disclaimer.

Mesri: ude. Contact author: Enrique A. Copyright notice. The publisher's final edited version of this article is available at Cell Host Microbe. See other articles in PMC that cite the published article. Abstract Approximately twelve percent of all human cancers are caused by oncoviruses. Open in a separate window. Figure 1. Oncovirus replication and persistence strategies involve activation of cancer-causing pathways Co-evolution of oncoviruses and their hosts is a fight for survival.

Table 1 Cancer Hallmarks activation by human viral oncogenes The table shows established viral oncogenes, the main cellular pathways they regulate and the cancer hallmarks they can potentially induce.

Molecular mechanisms of EBV oncogenesis: Cancer hallmarks activation at every stage The latency patterns of EBV are associated with specific lymphoma subtypes.

Figure 2. Latency I Burkitt's lymphoma BL. Figure 3. HPV-multistep carcinogenesis Although the replication strategy of high-risk human papillomaviruses requires modulation of cellular pathways that impinge on multiple cancer hallmarks Table I , expression of the viral transforming proteins is tightly controlled during normal productive HPV infections and infected cells only rarely undergo malignant transformation.

Molecular mechanisms of viral hepatocarcinogenesis The pathogenesis of HCC is a combination of direct and indirect mechanisms, which results from chronic oxidative damage that promotes the development of mutations.

Figure 4. Figure 5. Figure 6. Genetic instability vIRF-1 inhibits ATM activation of p53 to suppress DNA damage-induced apoptosis, a response that can lead to accumulation of mutations and genetic instability Shin et al. Sustained angiogenesis Prominent angiogenesis is a typical characteristic of KS. Preventing and targeting viral oncogenesis in the clinical setting Virus-induced cancers are amenable to immunoprophylaxis by vaccines Schiller and Lowy, Table 2 Therapeutic and preventive approaches successfully used to prevent and target oncoviral infections or their cancer associated hallmarks.

Conclusion Human viral cancers are pathobiological consequences of infection with viruses that evolved powerful mechanisms to persist and replicate through deregulation of host oncogenic pathways, conveying cancer hallmarks to the infected cell. Acknowledgements We thank Drs. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.

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The most recent virus types linked to human cancers are represented by Hepatitis C virus Choo et al. There exist good reasons to argue that still other virus types are involved in human cancers: Human immunodeficiency viruses types I and II induce severe immunosuppression and facilitate cancer induction by other persisting infections, in particular by HHV-8, Epstein-Barr virus and human papillomaviruses.

Thus, these agents contribute indirectly to human carcinogenesis. It is likely, in addition, that specific cutaneous papillomavirus infections contribute indirectly to skin carcinogenesis by blocking apoptosis in cells exposed to ultraviolet light Jackson and Storey, At present it is difficult to apply stringent criteria for the identification of human tumor viruses.

Commonly, these agents are strictly host-specific and several of them cannot be maintained under tissue culture conditions. The application of Koch's postulates therefore turns out to be impossible. Several attempts have been made to redefine criteria to determine the role of viruses in human carcinogenesis Evans, ; zur Hausen, a ; Vonka, Major problems arise due to direct and indirect modes of interaction in cell transformation.

For these reasons it appears to be useful to differentiate between these two alternatives. If we understand a direct contribution as expression of specific viral oncogenes or the selective insertion of viral nucleic acid into defined cellular genes, the following criteria seem to be useful modified from zur Hausen a :. The regular presence and persistence of the respective viral DNA in tumor biopsies and cell lines derived from the same tumor type;. The demonstration of growth-promoting activity of specific viral genes or of virus-modified host cell genes in tissue culture systems or in suitable animal systems;.

The demonstration that the malignant phenotype depends on the continuous expression of viral oncogenes or on the modification of host cell genes containing viral sequences;. Epidemiological evidence that the respective virus infection represents a major risk factor for cancer development. It is more difficult to develop stringent criteria for agents acting as indirect carcinogens. Here an evaluation depends on epidemiological data, on experimental results explaining possible modes of interaction e.

The identification here is usually more a question of plausibility than of a stringent experimental deduction. Our understanding of virus-induced oncogenesis has substantially increased during the past two decades. The emerging picture reveals a remarkable variation in mechanistic contributions. In addition, however, their own expression is tightly regulated by cellular factors and depends on the state of differentiation of infected keratinocytes. The interruption of this cellular control in infected basal layer cells emerges as a prime factor in cell immortalization, but also in malignant conversion reviewed in zur Hausen, b , Infections by Epstein—Barr virus and human Herpesvirus type 8 similarly result in the induction of viral oncogenes that affect a large number of host cell proteins.

The transforming mechanism, however, differs since other signaling cascades are modified. The regulation of viral gene expression by cellular factors has been less intensively studied in comparison to human papillomaviruses.

Yet, it is an interesting observation that overexpression of the cellular myc gene results in a Burkitt-like phenotype of the respective cells, suppressing the expression most EBNA genes, but permitting the expression of EBNA 1 Polack et al. The contribution of Hepatitis B virus to the development of hepatocellular carcinoma is presently poorly understood. It is still not possible to assign a direct or indirect role of this virus to human carcinogenesis.

Although a large number of liver cancer biopsies in Hepatitis B-endemic regions contain fragments of the viral genome, no consistent pattern has been observed up to now see review Arbuthnot and Kew, As an alternative explanation, the virus may act as an indirect carcinogen by mediating a chronic inflammation of the affected liver inducing an abundant production of reactive oxygen radicals.